Fatty amine drug conjugates

ABSTRACT

The invention provides conjugates of fatty amines and pharmaceutical agents useful in treating cancer, viruses, psychiatric disorders. Compositions, pharmaceutical preparations, and methods of preparations of the fatty amine-pharmaceutical agent conjugates are provided.

RELATED APPLICATION

[0001] This application claims priority under 35 U.S.C. §119 (e) fromU.S. provisional patent application Serial No. 60/278,552, filed on Mar.23, 2001, entitled Fatty Amine Drug Conjugates. The contents of theprovisional application are expressly incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to conjugates of fatty amines andpharmaceutical agents such as anticancer, antiviral, and antipsychoticagents useful, for example, in treating cancer, viruses, and psychiatricdisorders, and compositions and formulations thereof. Methods for makingand using the conjugates also are provided.

BACKGROUND OF THE INVENTION

[0003] Improving drug selectivity for target tissue is an establishedgoal in the medical arts. In general, it is desirable to deliver a drugselectively to its target, so that dosage and, consequently, sideeffects can be reduced. This is particularly the case for toxic agentssuch as anticancer agents because achieving therapeutic doses effectivefor treating the cancer is often limited by the toxic side effects ofthe anticancer agent on normal, healthy tissue.

[0004] Extensive research has been done on the use of fatty acids asagents that improve selectivity of drugs for their target tissues. Fattyacids previously have been conjugated with drugs to help the drugs asconjugates cross the blood brain barrier. DHA (docosahexaenoic acid) isa 22 carbon naturally-occurring, unbranched fatty acid that previouslyhas been shown to be unusually effective, when conjugated to a drug, incrossing the blood brain barrier. DHA is attached via the acid group tohydrophilic drugs and renders these drugs more hydrophobic (lipophilic).The mechanism of action by which DHA helps drugs conjugated to it crossthe blood brain barrier is unknown.

[0005] Another example of the conjugation of fatty acids to a drug isthe attachment of pipotiazine to stearic acid, palmitic acid, enanthicacid, undecylenic acid or 2,2-dimethyl-palmitic acid. Pipotiazine is adrug that acts within the central nervous system. The purpose ofconjugating pipotiazine to the fatty acids was to create an oilysolution of the drug as a liquid implant for slow release of the drugwhen injected intramuscularly. The release of the drug appeared todepend on the particular fatty acid selected, and the drug was testedfor its activity in the central nervous system.

[0006] Lipidic molecules, including fatty acids, also have beenconjugated with drugs to render the conjugates more lipophilic than theunconjugated drugs. In general, increased lipophilicity has beensuggested as a mechanism for enhancing intestinal uptake of drugs intothe lymphatic system, thereby enhancing the entry of the conjugate intothe brain and also thereby avoiding first-pass metabolism of theconjugate in the liver. The type of lipidic molecules employed haveincluded phospholipids, non-naturally occurring branched and unbranchedfatty acids, and naturally occurring branched and unbranched fatty acidsranging from as few as 4 carbon atoms to more than 30 carbon atoms. Inone instance, enhanced receptor binding activity was observed (for anadenosine receptor agonist), and it was postulated that the pendantlipid molecule interacted with the phospholipid membrane to act as adistal anchor for the receptor ligand in the membrane micro environmentof the receptor. This increase in potency, however, was not observedwhen the same lipid derivatives of adenosine receptor antagonists wereused, and generalizations thus were not made possible by those studies.

[0007] Of key importance in the treatment of cancer, viruses, andpsychiatric illness is the selectivity and targeting of drugs totissues. The increased targeting reduces the amount of pharmaceuticalagents needed, and the frequency of administration of the pharmaceuticalagents, both features especially important in treatments that involveadministration of pharmaceutical agents that may be toxic to surroundingtissues and may cause side effects. Because of the critical importanceof effective treatments for cancer, viral diseases and psychiatricdisorders and the difficulty in selectively targeting the affectedtissues, there is presently a need for effective methods to targettissues with powerful drugs, while also reducing the side effects anddifficult administration regimens.

[0008] Fatty amines are lipidic molecules terminating in an amino group(unlike fatty acids, which, of course, terminate in a carboxylic acidgroup). Unlike fatty acids, fatty amines are not a prevalent tissuecomponent of mammals. They typically are prepared synthetically usingfatty acids as a starting material.

SUMMARY OF THE INVENTION

[0009] The invention relates to the surprising discovery that fattyamines can be conjugated to pharmaceutical agents for treatment of avariety of disorders, including but not limited to cancer, viralinfections, and psychiatric diseases. The benefits of thesepharmaceutical-fatty amine conjugates include one or more of thefollowing: targeting of the drug to the tissue of interest; favorablyaffecting the volume of distribution of the drug in the tissue ofinterest; reducing toxicity of the drug; reducing side effects of thedrug; reducing clearance of the drug; reducing the necessary volumeand/or frequency of administration of the drug, or increasing the amountof drug that a subject can tolerate by favorably affecting volume ofdistribution, tissue distribution, and/or release kinetics of activedrug from an inactive conjugate in certain embodiments. Anothersurprising aspect of the fatty amine-pharmaceutical agent conjugates isthat once the fatty amines are separated from conjugation to thepharmaceutical agents in vivo, the fatty amines may be metabolized andeliminated.

[0010] Any and all of these aforementioned characteristics of the fattyamine-pharmaceutical agent conjugates may benefit subjects in need oftreatment for diseases such as cancer, psychiatric disorders, and viraldiseases and may allow altered dosages of drugs to be administered lessfrequently, with better results and fewer side effects.

[0011] According to one aspect of the invention, compositions of matterare provided. The compositions, or compounds, comprise pharmaceuticalagents (i.e., drugs) conjugated to fatty groups of fatty amines via acarbamate linkage and have the following formula:

[0012] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XOH.

[0013] According to another aspect of the invention, pharmaceuticalagents conjugated to fatty amines via phosphoramide linkages areprovided. The compounds have the formula:

[0014] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Z isO, a primary amino group, or a secondary amino group, and R′ is H, anion, or a protecting group.

[0015] According to another aspect of the invention, pharmaceuticalagents conjugated to fatty amines via phosphonamide linkages areprovided. The compounds have the formula:

[0016] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of a pharmaceutical agent XCH₂PO₃H₂,XCHR′PO₃H₂, or XCR′R″PO₃H₂, wherein R′ and R″ are independently selectedfrom alkyl, alkenyl, aryl, alkyl-substituted heteroatom,alkenyl-substituted heteroatom, an aryl-substituted heteroatom, and thelike.

[0017] According to another aspect of the invention, pharmaceuticalagents conjugated to fatty amines via urea (or carbamate) linkages areprovided. These compounds have the formula:

[0018] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Z isO, a primary amino group, or a secondary amino group.

[0019] According to another aspect of the invention, pharmaceuticalagents conjugated to fatty amines via amide linkages are provided. Thesecompounds have the following formula:

[0020] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XC(O)OH.

[0021] According to yet another aspect of the invention, pharmaceuticalagents conjugated to fatty amines via thionocarbamate linkages areprovided. These compounds are of the formula:

[0022] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XOH.

[0023] According to still another aspect of the invention,pharmaceutical agents linked to fatty amines via thiourea linkages areprovided. These compounds are of the formula:

[0024] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XNH₂.

[0025] According to yet another aspect of the invention, pharmaceuticalagents conjugated to fatty amines via guanidine linkages are provided.These compounds are of the formula:

[0026] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XNH₂ (or XOH).

[0027] In certain embodiments, the fatty amine moiety has a carbonstructure that is the same as the carbon structure of a naturallyoccurring fatty alcohol or acid. In some embodiments, the fatty aminemoiety has a carbon structure which is the same as the carbon structureof fatty acids which occur naturally in humans. Preferably, the fattyamine moiety has a carbon structure which is the same as a C₁₂-C₂₆, andeven more preferably a C₁₄-C₂₄, fatty acid occurring naturally inhumans.

[0028] In other embodiments, the fatty amine moiety has a carbonstructure that is the same as an unnatural fatty alcohol or acid. Insome embodiments, the fatty amine moiety has an even number of carbonatoms. In other embodiments, the fatty amine moiety has an odd number ofcarbon atoms. In some embodiments, the carbon structure is saturated andin other embodiments, the carbon structure is unsaturated (olefinic).Preferably, the carbon structure is unsaturated, that is, has at leastone double bond.

[0029] In some embodiments, the fatty amine moiety has a carbonstructure that is the same as any of the following fatty acids: caprylicacid, capric acid, undecylenic acid, lauric acid, myristic acid,palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenicacid, linoleic acid, linolenic acid, eleostearic acid, gondoic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid. These fatty acids encompass all of the various possibleisomers, including (E) and (Z) stereochemistry about the double bonds aswell as placement of the double bonds. For example, as used herein,linolenic acid encompasses γ-linolenic acid, dihomo-γ-linolenic acid, aswell as α-linolenic acid which differ by the placement of the doublebonds in the carbon chain but have the same molecular formula (andmolecular weight).

[0030] In some embodiments, the fatty amine moiety has a carbonstructure the same as a fatty acid selected from the group consistingof: octanoic (caprylic); nonanoic (pelargonic); decanoic (capric);undecanoic (hendecanoic); dodecanoic (lauric); tridecanoic;tetradecanoic (myristic); pentadecanoic; hexadecanoic (pamitic);heptadecanoic (margaric); octadecanoic (stearic); 12-hydroxy stearic;nonadecanoic; eicosanoic (arachidic); heneicosanoic; docosanoic(behenic); tricosanoic; and tetracosanoic (lignoceric).

[0031] In these and other embodiments, the fatty amine moiety has acarbon structure the same as a fatty acid selected from the groupconsisting of: 10-undecenoic (hendecenoic); 11-dodecenoic;12-tridecenoic; 9-tetradecenoic (myristoleic); 9-trans-tetradecenoic(myristelaidic); 10-pentadecenoic; 10-trans-pentadecenoic;9-hexadecenoic (palmitoleic); 8-trans-hexadecenoic (palmitelaidic);10-heptadecenoic; 10-trans-heptadecenoic; 6-octadecenoic (petroselinic);6-trans-octadecenoic (petroselaidic); 8-octadecenoic (oleic);9-11-octadecenoic (vaccenic); 11-trans-octadecenoic (transvaccenic);9-cis-12 hydroxy-octadecenoic (ricinoleic);9-trans-12-hydroxy-octadecenois (ricinelaidic); 7-nonadecenoic;7-trans-nonadecenoic; 10-nonadecenoic; 10-trans-nonadecenoic;10-13-nonadecadienoic; 10-13-trans-nona-decadienoic;8-12-octadecadienoic (linoleic); 9-trans-12-trans octadecadienoic(linoelaidic); octadecadienoic (conjugated); 9-12-15-octadecatrienoic(linolenic); 6-9-12-octadecatrienoic (gamma linolenic);11-trans-eicosenoic; 8-eicosenoic; 11-eicosenoic; 5-eicosenoic;11-14-eicosadienoic; 8-11-14-eicosatrienoic (homogamma linolenic);11-14-17-eicosatrienoic; 5-8-11-14-eicosatetraenoic (arachidonic);5-8-11-14-17-eicosapentaenoic; 7-10-13-16-19-docosapentaenoic;arachidonic; 13-docosenoic (erucic); 13-transdocosenoic (brassidic);13-16-docosadienoic; 13-16-19-docosatrienoic;7-10-13-16-docosatetraenoic; 4-7-10-13-16-19-docosahexaenoic (DHA);12-heneicosenoic; 12-15-heneicosadienoic; 14-tricosenoic; and15-tetracosenoic (nervonic).

[0032] Many pharmaceutical agents are useful in the present invention.As those skilled in the art will recognize, any pharmaceutical agenthaving a group to which a fatty amine may be conjugated (either directlyor via a linkage as described) is useful in the present invention. Suchpharmaceutical agents contain groups such as —OH, —NH₂, —NHR′, —CO₂H,—SH, —PO₃H₂, and the like (wherein R′ denotes a group such as alkyl,aryl, alkenyl, alkynyl, etc.). Many pharmaceutical agents, such asflavopiridol, contain more than one group to which fatty amines may beconjugated. As those skilled in the art will recognize, it is possibleto choose which group of the pharmaceutical agent the fatty amine willbe conjugated to by using, for example, well know protection anddeprotection strategies. Generally, conjugation of just one fatty aminemoiety to one pharmaceutical agent is preferable, although one skilledin the art will recognize that conjugation of more than one fatty amineto one pharmaceutical agent is possible.

[0033] In certain embodiments, the pharmaceutical agent may be selectedfrom an adrenergic agent; adrenocortical steroid; adrenocorticalsuppressant; amine deterrent; aldosterone antagonist; amino acid;ammonia detoxicant; anabolic; analeptic; analgesic; androgen;anesthesia; anesthetic; anorectic; antagonist; anterior pituitarysuppressant; anthelmintic; anti-acne agent; anti-adrenergic;anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal;anti-anxiety; anti-arthritic; anti-asthmatic; anti-atherosclerotic;antibacterial; anticholelithic; anticholelithogenic; anticholinergic;anticoagulant; anticoccidal; anticonvulsant; antidepressant;antidiabetic; antidiarrheal; antidiuretic; antidote; anti-emetic;anti-epileptic; anti-estrogen; antifibrinolytic; antifingal;antiglaucoma agent; antihemophilic; antihemorrhagic; antihistamine;antihyperlipidemic; antihyperlipoproteinemic; antihypertensive;antihypotensive; anti-infective; anti-infective, topical;anti-inflammatory; antikeratinizing agent; antimalarial; antimicrobial;antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic,antineutropenic, antiobessional agent; antiparasitic; antiparkinsonian;antiperistaltic, antipneumocystic; antiproliferative; antiprostatichypertrophy; antiprotozoal; antipruritic; antipsychotic; antirheumatic;antischistosomal; antiseborrheic; antisecretory, antispasmodic;antithrombotic; antitussive; anti-ulcerative; anti-urolithic; antiviral;appetite suppressant; benign prostatic hyperplasia therapy agent; bloodglucose regulator; bone resorption inhibitor; bronchodilator; carbonicanhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic;cardiovascular agent; choleretic; cholinergic; cholinergic agonist;cholinesterase deactivator; coccidiostat; cognition adjuvant; cognitionenhancer; depressant; diagnostic aid; diuretic; dopaminergic agent;ectoparasiticide; emetic; enzyme inhibitor; estrogen; fibrinolytic;fluorescent agent; free oxygen radical scavenger; gastrointestinalmotility effector; glucocorticoid; gonad-stimulating principle; hairgrowth stimulant; hemostatic; histamine H2 receptor antagonists;hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive;imaging agent; immunizing agent; immunomodulator; immunoregulator;immunostimulant; immunosuppressant; impotence therapy adjunct;inhibitor; keratolytic; LNRH agonist; liver disorder treatment;luteolysin; memory adjuvant; mental performance enhancer; moodregulator; mucolytic; mucosal protective agent; mydriatic; nasaldecongestant; neuromuscular blocking agent; neuroprotective; NMDAantagonist; non-hormonal sterol derivative; oxytocic; plasminogenactivator; platelet activating factor antagonist; platelet aggregationinhibitor; post-stroke and post-head trauma treatment; potentiator;progestin; prostaglandin; prostate growth inhibitor; prothyrotropin;psychotropic; pulmonary surface; radioactive agent; regulator; relaxant;repartitioning agent; scabicide; sclerosing agent; sedative;sedative-hypnotic; selective adenosine A1 antagonist; serotoninantagonist; serotonin inhibitor; serotonin receptor antagonist; steroid;stimulant; suppressant; symptomatic multiple sclerosis; synergist;thyroid hormone; thyroid inhibitor; thyromimetic; tranquilizer; agentfor treatment of amyotrophic lateral sclerosis; agent for treatment ofcerebral ischemia; agent for treatment of Paget's disease; agent fortreatment of unstable angina; uricosuric; vasoconstrictor; vasodilator;vulnerary; wound healing agent; and xanthine oxidase inhibitor.

[0034] In certain important embodiments, the pharmaceutical agent is ananticancer agent. Important anticancer agents include: Acivicin;Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Adriamycin;Aldesleukin; Alitretinoin; Allopurinol Sodium; Altretamine; Ambomycin;Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole;Annonaceous Acetogenins; Anthramycin; Asimicin; Asparaginase; Asperlin;Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bexarotene;Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin;Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Bullatacin; Busulfan;Cabergoline; Cactinomycin; Calusterone; Caracemide; Carbetimer;Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin;Cedefingol; Celecoxib; Chlorambucil; Cirolemycin; Cisplatin; Cladribine;Crisnatol Mesylate; Cyclophospharnide; Cytarabine; Dacarbazine; DACA(N-[2-(Dimethyl-amino)ethyl]acridine-4-carboxamide); Dactinomycin;Daunorubicin Hydrochloride; Daunomycin; Decitabine; Denileukin Diftitox;Dexormiaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone;Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene;Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate;Eflomithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate;Epipropidine; Epirubicin Hydrochloride; Erbulozole; EsorubicinHydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole;Ethiodized Oil I 131; Etoposide; Etoposide Phosphate; Etoprine;Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine;Fludarabine Phosphate; Fluorouracil; 5-FdUMP; Flurocitabine; Fosquidone;Fostriecin Sodium; FK-317; FK-973; FR-66979; FR-900482; Gemcitabine;Gemcitabine Hydrochloride; Gemtuzumab Ozogamicin; Gold Au 198; GoserelinAcetate; Guanacone; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide;Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-n1;Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-I b;Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole;Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium;Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine;Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate;Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium;Methoxsalen; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;Mitogillin; Mitomalcin; Mitomycin; Mytomycin C; Mitosper; Mitotane;Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;Oprelvekin; Ormaplatin; Oxisuran; Paclitaxel; Pamidronate Disodium;Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate;Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride;Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine;Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride;Pyrazofurin; Riboprine; Rituximab; Rogletimide; Rolliniastatin;Safingol; Safingol Hydrochloride; Samarium/Lexidronam; Semustine;Simtrazene; Sparfosate Sodium; Sparsomycin; SpirogermaniumHydrochloride; Spiromustine; Spiroplatin; Squamocin; Squamotacin;Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; TeloxantroneHydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;Thiamiprine; Thioguanine; Thiotepa; Thymitaq; Tiazofurin; Tirapazamine;Tomudex; TOP-53; Topotecan Hydrochloride; Toremifene Citrate;Trastuzumab; Trestolone Acetate; Triciribine Phosphate; Trimetrexate;Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; UracilMustard; Uredepa; Valrubicin; Vapreotide; Verteporfin; Vinblastine;Vinblastine Sulfate; Vincristine; Vincristine Sulfate; Vindesine;Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate;Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate;Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; ZorubicinHydrochloride; 2-Chlorodeoxyadenosine; 2′-Deoxyformycin;9-aminocamptothecin; raltitrexed; N-propargyl-5,8-dideazafolic acid;2-chloro-2′-arabinofluoro-2′-deoxyadenosine; 2-chloro-2′-deoxyadenosine;anisomycin; trichostatin A; hPRL-G129R; CEP-751; linomide; sulfurmustard; nitrogen mustard (mechlor ethamine); cyclophosphamide;melphalan; chlorambucil; ifosfamide; busulfan; N-methyl-N-nitrosourea(MNU); N,N′-Bis(2-chloroethyl)-N-nitrosourea (BCNU);N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea (CCNU);N-(2-chloroethyl)-N′-(trans-4-methylcyclohexyl-N-nitrosourea (MeCCNU);N-(2-chloroethyl)-N′-(diethyl)ethylphosphonate-N-nitrosourea(fotemustine); streptozotocin; diacarbazine (DTIC); mitozolomide;temozolomide; thiotepa; mitomycin C; AZQ; adozelesin; Cisplatin;Carboplatin; Ormaplatin; Oxaliplatin; C1-973; DWA 2114R; JM216; JM335;Bis(platinum); tomudex; azacitidine; cytarabine; gemcitabine;6-Mercaptopurine; 6-Thioguanine; Hypoxanthine; teniposide; 9-aminocamptothecin; Topotecan; CPT-11; Doxorubicin; Daunomycin; Epirubicin;darubicin; mitoxantrone; losoxantrone; Dactinomycin (Actinomycin D);amsacrine; pyrazoloacridine; all-trans retinol;14-hydroxy-retro-retinol; all-trans retinoic acid; N-(4-Hydroxyphenyl)retinamide; 13-cis retinoic acid; 3-Methyl TTNEB; 9-cis retinoic acid;fludarabine and (2-F-ara-AMP); 2-chlorodeoxyadenosine (2-Cda).

[0035] Other anti-neoplastic compounds include 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bleomycin A₂; bleomycinB₂; bropirimine; budotitane; buthionine sulfoximine; calcipotriol;calphostin C; camptothecin derivatives (e.g., 10-hydroxy-camptothecin);canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; 2′deoxycoformycin(DCF); deslorelin; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; discodermolide;docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epothilones (A, R=H; B,R=Me); epithilones; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide; etoposide4′-phosphate (etopofos); exemestane; fadrozole; fazarabine; fenretinide;filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathioneinhibitors; hepsulfam; heregulin; hexamethylene bisacetamide;homoharringtonine (HHT); hypericin; ibandronic acid; idarubicin;idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones;imiquimod; immunostimulant peptides; insulin-like growth factor-1receptor inhibitor; interferon agonists; interferons; interleukins;iobenguane; iododoxorubicin; ipomeanol, 4-; irinotecan; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mithracin;mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxinfibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; monoclonal antibody, human chorionic gonadotrophin;monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multipledrug resistance gene inhibitor; multiple tumor suppressor 1-basedtherapy; mustard anticancer agent; mycaperoxide B; mycobacterial cellwall extract; myriaporone; N-acetyldinaline; N-substituted benzamides;nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;nartograstim; nedaplatin; nemorubicin; neridronic acid; neutralendopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxideantioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone;oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oralcytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin;paclitaxel analogues; paclitaxel derivatives; palauamine;palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin;pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;pentostatin; pentrozole; perflubron; perfosfamide; perillyl amine;phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetinB; plasminogen activator inhibitor; platinum complex; platinumcompounds; platinum-triamine complex; podophyllotoxin; porfimer sodium;porfiromycin; propyl bis-acridone; prostaglandin J2; proteasomeinhibitors; protein A-based immune modulator; protein kinase Cinhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl proteintransferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptinedemethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RIIretinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; signal transductionmodulators; single chain antigen binding protein; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfmosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thalidomide; thiocoraline; thrombopoietin; thrombopoietinmimetic; thymalfasin; thymopoictin receptor agonist; thymotrinan;thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;titanocene dichloride; topotecan; topsentin; toremifene; totipotent stemcell factor; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; vector system, erythrocyte genetherapy; velaresol; veramine; verdins; verteporfin; vinorelbine;vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; andzinostatin stimalamer.

[0036] Other anticancer agents include antiproliferative agents (e.g.,piritrexim isothionate), antiprostatic hypertrophy agent (e.g.,sitogluside), benign prostatic hyperplasia therapy agents (e.g.,tamsulosin hydrochloride), prostate growth inhibitor agents (e.g.,pentomone), and radioactive agents: fibrinogen I 125; fludeoxyglucose F18; fluorodopa F 18; insulin I 125; insulin I 131; iobenguane I 123;iodipamide sodium I 131; iodoantipyrine I 131; iodocholesterol I 131;iodohippurate sodium I 123; iodohippurate sodium I 125; iodohippuratesodium I 131; iodopyracet I 125; iodopyracet I 131; iofetaminehydrochloride I 123; iomethin I 125; iomethin I 131; iothalamate sodiumI 125; iothalamate sodium I 131; iotyrosine I 131; liothyronine I 125;liothyronine I 131; merisoprol acetate Hg 197; merisoprol acetate Hg203; merisoprol Hg 197; selenomethionine Se 75; technetium Tc 99mantimony trisulfide colloid; technetium Tc 99m bicisate; technetium Tc99m disofenin; technetium Tc 99m etidronate; technetium Tc 99mexametazime; technetium Tc 99m furifosmin; technetium Tc 99m gluceptate;technetium Tc 99m lidofenin; technetium Tc 99m mebrofenin; technetium Tc99m medronate; technetium Tc 99m medronate disodium; technetium Tc 99mmertiatide; technetium Tc 99m oxidronate; technetium Tc 99m pentetate;technetium Tc 99m pentetate calcium trisodium; technetium Tc 99msestamibi; technetium Tc 99m siboroxime; technetium Tc 99m succimer;technetium Tc 99m sulfur colloid; technetium Tc 99m teboroxime;technetium Tc 99m tetrofosmin; technetium Tc 99m tiatide; thyroxine I125; thyroxine I 131; tolpovidone I 131; triolein I 125; and triolein I131.

[0037] Another category of anticancer agents useful as pharmaceuticalagents in the present invention include anticancer supplementarypotentiating agents. Anticancer supplementary potentiating agentsinclude tricyclic anti-depressant drugs (e.g., imipramine, desipramine,amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline,protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressantdrugs (e.g., sertraline, trazodone and citalopram); Ca⁺⁺ antagonists(e.g., verapamil, nifedipine, nitrendipine and caroverine); calmodulininhibitors (e.g., prenylamine, trifluoroperazine and clomipramine);amphotericin B; triparanol analogues (e.g., tamoxifen); antiarrhythmicdrugs (e.g., quinidine); antihypertensive drugs (e.g., reserpine); thioldepleters (e.g., buthionine and sulfoximine) and multiple drugresistance reducing agents such as Cremaphor EL.

[0038] One particularly preferred class of anticancer agents for use inthe present invention are taxanes. Among the taxanes, paclitaxel anddocetaxel are preferred. Another preferred anticancer agent for use inthe present invention is flavopirodol. Other important anticancer agentsare annonaceous acetogenins and SN-38.

[0039] Another category of pharmaceutical agents for use in the presentinvention is antipsychotic agents. Antipsychotic agents includelorazepam; chlordiazepoxide; clorazepate; diazepam; alprazolam;hydroxyzine; buspirone; venlafaxine; mephobarbital; meprobamate;doxepin; perphenazine; hydroxyzine pamoate; venlafaxine; mirtazapine;nefazodone; bupropion; phenelzine; tranylcypromine; citalopram;paraxefine; sertraline; amitrptyline; protriptyline; divalproex;clonazepam; clozapine; haloperidol; loxapine; molindone; thiothixene;pimozide; risperidone; quefiapine; thiothixen; olanzapine; quetiapine;prochlorperazine; mesoridazin; trifluoperazine; chlorpromazine;perphenazine; and fluvoxamine.

[0040] Another category of pharmaceutical agents useful in the presentinvention is antiviral agents. Antiviral agents include nucleosideanalogs, nonnucleoside reverse transcriptase inhibitors, proteaseinhibitors, integrase inhibitors, including the following: Acemannan;Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox;Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate;Avridine; BRL 47923; BRL 44385; Cidofovir; Cipamfylline; CytarabineHydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril;Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride;Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium;Ganciclovir; Ganciclovir Sodium; Idoxuridine; Indinavir; Kethoxal;Lamivudine; Lobucavir; Memotine Hydrochloride; Methisazone; Nelfinavir;Nevirapine; Penciclovir; Pirodavir; Ribavirin; RimantadineHydrochloride; Ritonavir; Saquinavir Mesylate; SomantadineHydrochloride; 7-hydroxystaurosporine, Sorivudine; Statolon; Stavudine;Tilorone Hydrochloride; Trifluridine; Valacyclovir Hydrochloride;Vidarabine; Vidarabine Phosphate; Vidarabine Sodium Phosphate; Viroxime;Zalcitabine; Zidovudine; Zinviroxime, and integrase inhibitors.Adefovir, cidofovir, BRL 47923, and BRL 44385 are particularly importantpharmaceutical agents.

[0041] Particularly preferred pharmaceutical agents useful in thepresent invention include: annonaceous acetogenins; asimicin;rolliniastatin; guanacone, squamocin, bullatacin; squamotacin; taxanes;methotrexate FR-900482; FK-973; 3, FR-66979; FK-317; 5-FU; FUDR; FdUMP;Hydroxyurca; meta-pac; irinotecan; SN-38; 10-OH campto; topotecan;adriamycin; cis-Pt; carbo-Pt; bleomycin; mitomycin C; mithramycin;capecitabine; cytarabine; 2-Cl-2′deoxyadenosine; fludarabine-PO₄;mitoxantrone; mitozolomide; pentostatin; tomudex, TMC-125, TMC-114,valganciclovir; fomivirsen; zanamivir; oseltamivir; rimantidine;adefovir dipivoxil; tenofovir; tenofovir disoproxil;viramidine;3-deazaneplanocin A; neplanocin A; saquanivir; maribavir;N-methanocarbathymidine; fusaric acid; synguanol; glycyrrhyzic acid;fludaribine; entecavir; and MIV-210.

[0042] Other particularly preferred pharmaceutical agents for use in thepresent invention include: gemcitabine, docetaxel, paclitaxel,vincristine, vinblastine, vinorelbine, SN-38, BRL 47923, BRL 44385,cidofivor, anhydrovinblastine, flavopiridol, purvalanol A, purvalanol B,aminopurvalanol, roscovitine, etoposide, 7-ethyl-10-hydroxycamptothecin,10-hydroxycamptothecin, doxorubicin, mitomycin C, mithracin, epothiloneB, epothilone D, camptothecin, discodermolide, and adefovir (PMEA).

[0043] One skilled in the art will readily recognize thosepharmaceutical agents are suitable for conjugation with fatty amineswith no more than routine skill. For example, one skilled in the artwill recognize that flavopiridol does not contain a carboxylic acidmoiety and as a result, it is inconvenient to synthesize a conjugatewith an amide linkage. Preferred pharmaceutical agents are shown inTable 1, along with preferred linkages. TABLE 1 FATTY AMINEPHARMACEUTICAL AGENT CONJUGATES Carba- Phosphor- Thio- mate amide Ureaurea Paclitaxel X X Docetaxel X X Gemcitabine X X X X Vincristine X X XX Vinblastine X X X X Camptothecin X X CPT-11 X X SN-38 X X Mitomycin CX X X Doxorubicin X X X X Adefovir X X X BRL 47923 X X X BRL 44385 X X XX Roscovotine X X X X Purvalanol A X X X X Puvalanol B X X X XFlavopiridol X X Cidofovir X X X X Ribavirin X X Amide ThionocarbamatePhosphonamide Paclitaxel X Docetaxel X Gemcitabine X Vincristine X XVinblastine X X Camptothecin X CPT-11 X SN-38 X Mitomycin C DoxorubicinX Adefovir X BRL 47923 X BRL 44385 X Roscovotine X Purvalanol A XPuvalanol B X X Flavopiridol X Cidofovir X X Ribavirin X

[0044] Although the above examples are preferred, they are not limiting.Other conjugates may be synthesized according to the invention.

[0045] According to another aspect of the invention, compositions ofmatter are provided. The compositions are useful as intermediates tofatty amine pharmaceutical agent conjugates and are isocyanates of thefollowing formula:

R—N═C═O

[0046] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂.

[0047] According to another aspect of the invention, compounds useful asintermediates to the pharmaceutical agent fatty amine conjugates of theformula:

[0048] are provided wherein R is a C₈-C₂₆ group of a fatty amine RNH₂,R′ is H, an ion, or a protecting group and T is a leaving group.

[0049] According to yet another aspect of the invention, compounds whichare useful as intermediates in the synthesis of pharmaceutical agentfatty amine conjugates are provided. These compounds are of the formula:

[0050] wherein R is a C₈-C₂₆ group of a fatty amine RNH₂, T is a leavinggroup, and BOC is a tert-butoxy group.

[0051] In certain embodiments, the leaving group T is OH, a halogen, oranother leaving group. Particularly important leaving groups includeN-hydroxysuccinimidyl, N-hydroxphthalimidyl, imidazoyl,para-nitrophenyl, ortho-nitrophenyl, azido, hydroxybenzotriazolyl,chloro, fluoro, N-hydroxymaleimidyl, pentafluorophenyl,2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 1-hydroxypiperidinyl,pentacholorphenyl, 3,4,5-trimethoxyphenyl, hydroxypyridinyl,4-dimethylaminopyridinyl, 1-triazolopyridinyl, pyrazolyl,3,5-dimethylpyrazolyl, and 1H-1,2,3-triazaolo-[4,5-b]pyridinyl. Theseleaving groups may optionally be substituted with electron withdrawinggroups or electron donating groups. Other leaving groups include, butare not limited to:

[0052] The fatty amines and fatty amine moieties of important andpreferred embodiments are as described above, as if specificallyrestated herein.

[0053] Those of skill in the art will appreciate that variousmodifications to the synthetic methods described are possible, andincluded in the invention. Such modifications include, for example,polymer supported, or solid phase, chemistry.

[0054] According to another aspect of the invention, pharmaceuticalpreparations of all of the compositions described herein are provided.In one embodiment, the pharmaceutical preparation comprises a compoundof the formula:

[0055] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, and X isa pharmaceutical agent moiety of the pharmaceutical agent XOH, and apharmaceutically acceptable carrier.

[0056] In another aspect of the invention, pharmaceutical preparationscomprising a compound of the formula:

[0057] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Z isO, a primary amino group, or a secondary amino group, and R′ is H, anion, or a protecting group, and a pharmaceutically acceptable carrierare provided.

[0058] In another aspect of the invention, pharmaceutical preparationscomprising a compound of the formula:

[0059] pharmaceutically acceptable carrier are provided wherein R is aC₈-C₂₆ fatty group of a fatty amine RNH₂, X is a pharmaceutical agentmoiety of a pharmaceutical agent XCH₂PO₃H₂, XCHR′PO₃H₂, or XCR′R″PO₃H₂,wherein R′ and R″ are independently selected from alkyl, alkenyl, aryl,alkyl-substituted heteroatom, alkenyl-substituted heteroatom, anaryl-substituted heteroatom, and the like.

[0060] According to still another aspect of the invention,pharmaceutical preparations comprising a compound of the formula:

[0061] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Zis O, a primary amino group, or a secondary amino group and apharmaceutically acceptable carrier are provided.

[0062] According to yet another aspect of the invention, pharmaceuticalpreparations comprising a compound of the formula:

[0063] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XC(O)OH and apharmaceutically acceptable carrier are provided.

[0064] According to still another aspect of the invention,pharmaceutical preparations comprising a compound of the formula:

[0065] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XOH and apharmaceutically acceptable carrier are provided.

[0066] According to another aspect of the invention, pharmaceuticalpreparations comprising a compound of the formula:

[0067] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XNH₂ and apharmaceutically acceptable carrier are provided.

[0068] According to another aspect of the invention, pharmaceuticalpreparations comprising a compound of the formula:

[0069] wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X isa pharmaceutical agent moiety of a pharmaceutical agent XNH₂ and apharmaceutically acceptable carrier are provided.

[0070] The fatty amines and fatty amine moieties of important andpreferred embodiments are as described above, as if specificallyrestated herein.

[0071] Certain embodiments of the pharmaceutical agent categories are aslisted above, and particularly important categories are anticanceragents, antipsychotic agents and antiviral agents. Important such agentsand preferred embodiments are as described above, as if specificallyrestated herein.

[0072] According to another aspect of the invention, methods fortreating disorders are provided. In one aspect, methods of treatingdisorders comprising administering to a subject in need of suchtreatment a pharmaceutical preparation comprising a compound of theformula:

[0073] and a pharmaceutically acceptable carrier wherein R is a C₈-C₂₆fatty group of a fatty amine RNH₂, and X is a pharmaceutical agentmoiety of the pharmaceutical agent XOH.

[0074] In another aspect of the invention, methods for treating adisorder comprising administering to a subject in need of such treatmenta pharmaceutical preparation comprising a compound of the formula:

[0075] and a pharmaceutically acceptable carrier are provided wherein Ris a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is a pharmaceuticalagent moiety of a pharmaceutical agent XZH, wherein Z is O, a primaryamino group, or a secondary amino group, and R′ is H, an ion, or aprotecting group.

[0076] In another aspect of the invention, methods of treating disorderscomprising administering to a subject in need of such treatment apharmaceutical preparation comprising a compound of the formula:

[0077] and a pharmaceutically acceptable carrier are provided wherein Ris a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is a pharmaceuticalagent moiety of a pharmaceutical agent XZH, wherein Z is O, a primaryamino group, or a secondary amino group.

[0078] In another aspect of the invention, methods of treating disorderscomprising administering to a subject in need of such treatment apharmaceutical preparation comprising a compound of the formula:

[0079] and a pharmaceutically acceptable carrier are provided wherein Ris a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is a pharmaceuticalagent moiety of a pharmaceutical agent XC(O)OH and a pharmaceuticallyacceptable carrier.

[0080] In another aspect of the invention, methods of treating disorderscomprising administering to a subject in need of such treatment apharmaceutical preparation comprising a compound of the formula:

[0081] and a pharmaceutically acceptable carrier are provided wherein Ris a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is a pharmaceuticalagent moiety of a pharmaceutical agent XOH.

[0082] In another aspect of the invention, methods of treating disorderscomprising administering to a subject in need of such treatment apharmaceutical preparation comprising a compound of the formula:

[0083] and a pharmaceutically acceptable carrier are provided wherein Ris a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is a pharmaceuticalagent moiety of a pharmaceutical agent XNH₂.

[0084] In still another aspect of the invention, methods of treatingdisorders comprising administering to a subject in need of suchtreatment a pharmaceutical preparation comprising a compound of theformula:

[0085] and a pharmaceutically acceptable carrier are provided wherein Ris a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is a pharmaceuticalagent moiety of a pharmaceutical agent XNH₂.

[0086] The fatty amines and fatty amine moieties of important andpreferred embodiments are as described above, as if specificallyrestated herein.

[0087] Certain embodiments of the pharmaceutical agent categories are aslisted above, and particularly important categories are anticanceragents, antipsychotic agents and antiviral agents. Important such agentsand preferred embodiments are as described above, as if specificallyrestated herein.

[0088] In certain embodiments, the disorder is a mammalian cellproliferative disorder, a mammalian viral disorder, or mammalianpsychiatric disorder.

[0089] According to another aspect of the invention, methods ofsynthesizing fatty amine pharmaceutical agent conjugate compounds areprovided. Generally, the methods involve derivatizing a fatty amine withan appropriate linkage and leaving group to form an intermediate andreacting the intermediate with a pharmaceutical agent to form theconjugate compound. Alternatively, the pharmaceutical agent may bederivatized with an appropriate linkage and leaving group and reactedwith a fatty amine to form the conjugate compound.

[0090] Generally, it is preferred to couple the fatty amine with alinkage and leaving group before conjugating the fatty amine with thepharmaceutical agent. As will be clear to those skilled in the art,other reactive groups of the pharmaceutical agent besides the site to beconjugated may have to be protected, which can be accomplished byroutine methods known in the art, as described in, for example, Greene,T. W., et al., In “Protective Groups in Organic Synthesis”, 3rd Ed.,John Wiley & Sons, Inc., New York, N.Y.; 1999, hereby incorporated byreference. Nonetheless, several representative synthetic methods andschemes are shown in the Examples.

[0091] In one embodiment, a method of synthesizing a pharmaceuticalagent conjugated to a fatty amine via a carbamate linkage is provided.The method comprises reacting an intermediate compound of the formulaR—N═C═O with a pharmaceutical agent of the formula XOH for a timesufficient to form the conjugate wherein R is a C₈-C₂₆ fatty group of afatty amine RNH₂ and X is a pharmaceutical agent moiety of thepharmaceutical agent of the formula XOH. Representative methods ofsynthesizing the isocyanate intermediate compound are shown in theExamples.

[0092] In another embodiment, a method of synthesizing a pharmaceuticalagent conjugated to a fatty amine via a phosphoramide linkage isprovided. The method comprises reacting an intermediate of the formula:

[0093] with a pharmaceutical agent XZH for a time sufficient to form thecompound wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of the pharmaceutical agent XZH, wherein Zis O, a primary amino group, or a secondary amino group, and R′ is H, anion, a protecting group or a second pharmaceutical agent.

[0094] Alternatively, the pharmaceutical agent fatty amine conjugatesmay be synthesized by first derivatizing the pharmaceutical agent at acarboxylic acid group with a phosphate leaving group moiety and thencoupling to a fatty amine. Although both methods may be accomplishedusing techniques known to those of skill in the art, exemplary syntheticmethods are also provided in the Examples.

[0095] In another embodiment, a method of synthesizing a pharmaceuticalagent conjugated to a fatty amine via a phosphonamide linkage isprovided. The method comprises reacting an fatty amine RNH₂ with apharmaceutical agent XCH₂PO₃H₂, XCHR′PO₃H₂, or XCR′R″PO₃H₂, wherein R′and R″ are independently selected from alkyl, alkenyl, aryl,alkyl-substituted heteroatom, alkenyl-substituted heteroatom, anaryl-substituted heteroatom, and the like. As one skilled in the artwill recognize, the pharmaceutical agent may be manipulated first, asshown in the Examples.

[0096] According to yet another embodiment of the invention, a method ofmaking a pharmaceutical agent conjugated to a fatty amine via a urealinkage is provided. The method comprises reacting an intermediate ofthe formula R—N═C═O with a pharmaceutical agent of the formula XZH for atime sufficient to form the compound wherein R is a C₈-C₂₆ fatty groupof a fatty amine RNH₂, X is a pharmaceutical agent moiety of thepharmaceutical agent and Z is O, a primary amino group, or a secondaryamino group.

[0097] According to still another embodiment of the invention, methodsof making pharmaceutical agents conjugated to fatty amines via amidelinkages are provided. Thus, a pharmaceutical agent containing acarboxylic acid moiety is treated with an activating agent such as1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base(4-Dimethylaminopyridine) to give the corresponding active acylintermediate. Addition of a fatty amine to said active acyl intermediateprovides the fatty amine-derived amide conjugated pharmaceutical agent.

[0098] According to yet another aspect of the invention, methods ofmaking fatty amines conjugated to pharmaceutical agents viathionocarbamate linkages are provided. Thus, a fatty amine is treatedwith thiophosgene (or a similar reagent such as di-2-pyridylthionocarbonate or di-N-hydroxysuccinimidyl thionocarbonate) prior toreaction with a pharmaceutical agent containing a hydroxyl group. Insimilar but reverse fashion, a pharmaceutical agent containing ahydroxyl group is treated with thiophosgene (or a similar reagent suchas di-2-pyridyl thionocarbonate or di-N-hydroxysuccinimidylthionocarbonate) prior to reaction with a fatty amine. Both methodsprovide equivalent thionocarbamate conjugates.

[0099] According to still another aspect of the invention, methods ofmaking fatty amines conjugated to pharmaceutical agents via thiourealinkages are provided. Thus, a fatty amine is first treated with1,1′-thiocarbonyldiimidazole, followed by a pharmaceutical agent bearingan amino group.

[0100] According to still another aspect of the invention, methods ofmaking fatty amines conjugated to pharmaceutical agents via guanidinelinkages are provided. Thus, a pharmaceutical agent bearing a hydroxylgroup is treated under Mitsunobu conditions (PPh3,diethylazodicarboxylate, THF) with either1,3-bis(tert-butoxycarbonyl)guanidine or1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea, followed byaddition of the fatty amine, to provide the corresponding BOC-protectedguanidine. Subsequent deprotection using trifluoracetic acid furnishesthe desired guanidine connecting a pharmaceutical agent and a fattyamine.

[0101] The method comprises reacting a fatty amine RNH2 with aguanylation agent such as 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea or 1,3-bis(tert-butoxycarbonyl-1H-pyrazole-1-carboxamidine and reacting the resulting productwith a pharmaceutical agent of the formula XOH for a time sufficient toform the compound wherein R is a C₈-C₂₆ fatty group of the fatty amine,and X is the pharmaceutical agent moiety of a pharmaceutical agent ofthe formula XOH.

[0102] According to another aspect of the invention, a fattyamine-anticancer compound conjugate in some embodiments is believed tobe confined, unexpectedly, to the plasma space of a subject receivingsuch treatment, and that the conjugate has, surprisingly, (i) a smallervolume of distribution as compared to the unconjugated anticancercompound alone (in many instances ˜100 fold less), and (ii) a smallerclearance as compared to the unconjugated anticancer compound alone (inmany instances ˜100 fold less). Moreover, it is believed that the fattyamine-anticancer compound conjugate may be present at a higherconcentration in tumor cells as compared to the unconjugated anticancercompound.

[0103] Thus, a fatty amine-anticancer compound conjugate composition foradministration to a subject is provided. The composition includes atleast one fatty amine-anticancer compound conjugate in a container foradministration to a subject. The amount of the fatty amine-anticancercompound in the container is at least about 10% greater than the maximumtolerated dose (MTD) for the unconjugated at least one anticancercompound (based on the weight of the anticancer compound in theconjugate versus the weight of the anticancer compound itself, orcalculated on a molar basis of the conjugate versus the unconjugatedanticancer compound). Preferably the amount of the fattyamine-anticancer compound in the container is at least about 20% greaterthan the MTD, 30% greater than the MTD, 40% greater than the MTD, 50%greater than the MTD, 75% greater than the MTD, 100% greater than theMTD, 200% greater than the MTD, 300% greater than the MTD, or 400%greater than the MTD for the unconjugated at least one anticancercompound. In certain preferred embodiments, the container is a containerfor intravenous administration. In other embodiments, the anticancercompound is a taxane, preferably paclitaxel or docetaxel. In importantembodiments, the conjugate is not encapsulated in a liposome.

[0104] According to yet another aspect of the invention, a method fortreating a subject having an abnormal mammalian proliferative disorderis provided. The method involves administering to the subject a fattyamine-taxane conjugate in an amount of the conjugate which is at least250, 275, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850,900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350 or 1400mg/meter² of body surface area (BSA). In one embodiment, the amount isadministered to the subject over a period of 24 hours or less, 6 hoursor less, 3 hours or less, or 2 hours or less. In some embodiments, thefatty amine has a C₁₆-C₂₆ fatty amine carbon structure. In importantembodiments, the fatty amine has the carbon structure of a C₈-C₂₂unbranched, naturally occurring fatty acid. In certain particularlypreferred embodiments, the fatty amine has the same carbon structure aslinoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid,docosahexaenoic acid, 2-octanoate, 2-hexanoate, CH₃-hexanoate,CH₃-butanoate, or oleic acid. In preferred embodiments, the taxane ispaclitaxel. In important embodiments, when the taxane is paclitaxel, thefatty amine is conjugated at the 2′ OH position of paclitaxel.

[0105] In any of the foregoing embodiments, the maximum tolerated dosecan be determined according to procedures known to those of ordinaryskill in the art. The Maximum Tolerated Doses of many compounds arealready known. Some for known anticancer agents are listed below.

[0106] According to another aspect of the invention, a composition ofmatter is provided. The composition comprises a crystal of a conjugateof a polyunsaturated fatty amine and a drug. In preferred embodiments,the fatty amine has a carbon structure of a C₁₂-C₂₂ or C₁₆-C₂₂ fattyacid. In some embodiments the fatty amine has the carbon structure of anaturally-occurring, unbranched fatty acid. In certain embodiments, thefatty amine has the same carbon structure as the carbon structure oflinoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid,docosahexaenoic acid, 2-octanoate, 2-hexanoate, CH₃-hexanoate,CH₃-butanoate, or oleic acid.

[0107] In any of the foregoing embodiments, the drug can be among thoselisted below. The drug must contain a site (reactive group) amenable forconjugation to a fatty amine or to a fatty amine derivative as describedherein. Chemists of ordinary skill in the art can make suchdeterminations. The anticancer compound can be a taxane. In certainembodiments, the taxane is paclitaxel. In important embodiments, whenthe taxane is paclitaxel, the fatty amine is conjugated at the 2′ OHposition of paclitaxel.

[0108] The invention in another aspect provides compositions andformulations for administration to a subject, preferably a humansubject, containing amounts of a fatty amine-anticancer compoundconjugate which exceeds the maximum tolerated dose for the unconjugatedanticancer compound. The fatty amine-anticancer compound conjugatepreferably is in a container for administration to a subject. Preferablythe container is a container for intravenous administration, such as anIV bag.

[0109] The amount of the fatty amine-anticancer compound in thecontainer is at least about 10% greater than the MTD for theunconjugated compound. Preferably the amount of the fattyamine-anticancer compound in the container is at least about 20%, 30%,40%, 50%, 75%, 100%, 200%, 300% or 400% greater than the MTD for theunconjugated at least one anticancer compound. The anticancer compoundis preferably a taxane, particularly paclitaxel or docetaxel.

[0110] Although the conjugate may be encapsulated in a liposome, it ispreferred that the conjugate is not encapsulated by a liposome in someembodiments. The preferred subjects for the method are humans.

[0111] The conjugated anticancer compounds described herein are lesstoxic and more effective than the corresponding unconjugated anticancercompounds. Therefore the fatty amine-anticancer compound conjugates canbe administered in amounts which are equally toxic but more effective,or in doses which are equally effective and less toxic than thecorresponding unconjugated anticancer compounds. In general, conjugationof fatty amine to anticancer compounds permits an increase in themaximum tolerated dose relative to unconjugated anticancer compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0112] The invention described herein relates to the preparation offatty amine-pharmaceutical agent conjugates and methods of using theconjugates in the treatment of disease. The conjugates may be a directconjugate between the fatty amine and the pharmaceutical agent, such asby an ester bond, or via a linkage such as a carbonate phosphate,carbamate, guanidine, thionocarbamate, isourea, or urea linkage. Incertain embodiments the conjugate breaks apart in vivo into componentsthat are naturally occurring or that are readily metabolized intomolecules that are naturally occurring. This is a particularly desirableaspect of the invention.

[0113] The invention provides compositions of matter. The invention alsoprovides intermediates formed in the process of making the compositionsof matter. The invention also provides substantially pure crystals of aconjugate of a fatty amine and a pharmaceutical agent. The inventionalso encompasses methods of preparing and conjugating the fatty aminesand pharmaceutical agents. Examples of processes of making compositionsof matter, and the intermediates in the process, which are not intendedto be limiting is, for example, the synthesis of etopophos fatty aminephosphate ester (in the Examples). Several synthetic processes aredescribed herein, although one of skill in the art will recognize thatthere may be other possible synthetic methods.

[0114] In the preparation of the compositions, fatty amines may bereacted with pharmaceutical agents to produce conjugates. As usedherein, “reacting” a fatty amine (or a fatty amine intermediate) with apharmaceutical agent means the fatty amine and the pharmaceutical agentare contacted under appropriate conditions for a time sufficient toresult in the covalent conjugation of the pharmaceutical agent and thefatty amine (or the fatty amine intermediate). Such conditions encompassstandard chemistry methods, which may be determined by one of skill inthe art.

[0115] In the preparation of the compositions, certain of the reactantsmay have leaving groups. As used herein, the term “leaving group” meansa chemical moiety which is removed in the course of the reaction anddoes not form part of the conjugate. Leaving groups are well known inthe art. Thus, one of ordinary skill can select an appropriate leavinggroup with no more than routine skill.

[0116] Fatty amines can be synthesized, typically from fatty acids,natural or synthetic. As those skilled in the art will recognize, fattyamines are routinely prepared from the corresponding fatty acid bytreating the fatty acid with ammonia and heating to form a fatty amide,converting the amide to a fatty nitrile, and reducing the fatty nitrileto the fatty amide.

[0117] Thus, fatty amines can have the same carbon structure ofnaturally occurring polyunsaturated fatty acids but have a terminalamino group instead of the terminal acid group of the fatty acids (i.e.,are the amino form of polyunsaturated fatty acids). In some embodiments,the fatty amine preferably has the same carbon structure as a C₁₂-C₂₆unbranched, naturally occurring fatty acid. In other embodiments, thefatty amine preferably has the same carbon structure as the carbonstructure of a C₁₂-C₂₄ and unbranched naturally occurring fatty acids.In other words, the fatty amine may have 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 carbon atoms.

[0118] Alternatively, the fatty amine may have a carbon structure whichis the same as that of an unnatural fatty acid. The carbon structure mayhave an even or odd amount of carbons, (E) or (Z) stereochemistry abouteach double bond, and encompasses isomers of naturally occurring fattymoieties of naturally occurring fatty acids, formed by, for example,differing placement of the double bonds throughout the carbon chain. Itwill be obvious to those of skill in the art that various isomers of thefatty amines and fatty acids described are included. For example, thereare several isomers of linoleic acid, which differ in the placement ofthe double bonds.

[0119] Carbon structures of fatty amines useful in the present inventioninclude carbon structures of the following fatty acids: octanoic(caprylic); nonanoic (pelargonic); decanoic (capric); undecanoic(hendecanoic); dodecanoic (lauric); tridecanoic; tetradecanoic(myristic); pentadecanoic; hexadecanoic (pamitic); heptadecanoic(margaric); octadecanoic (stearic); 12-hydroxy stearic; nonadecanoic;eicosanoic (arachidic); heneicosanoic; docosanoic (behenic);tricosanoic; tetracosanoic (lignoceric).

[0120] Other carbon structures of fatty amines useful in the presentinvention include carbon structures of the following fatty acids:10-undecenoic (hendecenoic); 11-dodecenoic; 12-tridecenoic;9-tetradecenoic (myristoleic); 9-trans-tetradecenoic (myristelaidic);10-pentadecenoic; 10-trans-pentadecenoic; 9-hexadecenoic (palmitoleic);8-trans-hexadecenoic (palmitelaidic); 10-heptadecenoic;10-trans-heptadecenoic; 6-octadecenoic (petroselinic);6-trans-octadecenoic (petroselaidic); 8-octadecenoic (oleic);9-11-octadecenoic (vaccenic); 11-trans-octadecenoic (transvaccenic);9-cis-12 hydroxy-octadecenoic (ricinoleic);9-trans-12-hydroxy-octadecenois (ricinelaidic); 7-nonadecenoic;7-trans-nonadecenoic; 10-nonadecenoic; 10-trans-nonadecenoic;10-13-nonadecadienoic; 10-13-trans-nonadecadienoic; 8-12-octadecadienoic(linoleic); 9-trans-12-trans octadecadienoic (linoelaidic);octadecadienoic (conjugaged); 9-12-15-octadecatrienoic (linolenic);6-9-12-octadecatrienoic (gamma linolenic); 11-trans-eicosenoic;8-eicosenoic; 11-eicosenoic; 5-eicosenoic; 11-14-eicosadienoic;8-11-14-eicosatrienoic (homogamma linolenic); 11-14-17-eicosatrienoic;5-8-11-14-eicosatetraenoic (arachidonic); 5-8-11-14-17-eicosapentaenoic;7-10-13-16-19-docosapentaenoic; arachidonic; 13-docosenoic (erucic);13-transdocosenoic (brassidic); 13-16-docosadienoic;13-16-19-docosatrienoic; 7-10-13-16-docosatetraenoic;4-7-10-13-16-19-docosahexaenoic (DHA); 12-heneicosenoic;12-15-heneicosadienoic; 14-tricosenoic; 15-tetracosenoic (nervonic).

[0121] In certain important embodiments, the carbon structure of fattyamine can be the same as the carbon structure of: linoleic acid,palmitic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoicacid, 2-octanoate, 2-hexanoate, CH₃-hexanoate, CH₃-butanoate, or oleicacid. In particularly preferred embodiments, the fatty amine has thesame carbon structure as: linoleic acid, palmitic acid, arachidonicacid, eicosapentaenoic acid, or docosahexaenoic acid.

[0122] The methods and/or products of the invention are useful fortreating a variety of medical conditions. The conditions will beapparent from the list of drugs below. Among the conditions are abnormalmammalian-cell proliferation, psychosis, infectious disease,cardiovascular conditions, stroke, Alzheimer's disease, and dementia.One important embodiment is conditions involving abnormal mammalian cellproliferation. The methods and/or products of the invention may beuseful for treating cancers including, but not limited to, biliary tractcancer; bladder cancer; brain cancer including glioblastomas andmedulloblastomas; breast cancer; cervical cancer; choriocarcinoma; coloncancer; endometrial cancer; esophageal cancer; gastric cancer;hematological neoplasms including acute lymphocytic and myelogenousleukemia; multiple myeloma; AIDS-associated leukemias and adult T-cellleukemia lymphoma; intraepithelial neoplasms including Bowen's diseaseand Paget's disease; liver cancer; lung cancer; lymphomas includingHodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancerincluding squamous cell carcinoma; ovarian cancer including thosearising from epithelial cells, stromal cells, germ cells and mesenchymalcells; pancreatic cancer; prostate cancer; rectal cancer; sarcomasincluding leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma,and osteosarcoma; skin cancer including melanoma, Kaposi's sarcoma,basocellular cancer, and squamous cell cancer; testicular cancerincluding germinal tumors such as seminoma, non-seminoma (teratomas,choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancerincluding thyroid adenocarcinoma and medullar carcinoma; and renalcancer including adenocarcinoma and Wilms tumor.

[0123] The products and/or methods of the invention are useful, ingeneral, for treating mammalian cell proliferative disorders other thancancer including psoriasis, actinic keratosis, etc. They further areuseful in treating diabetes and its complications, excess acidsecretion, cardiovascular conditions involving cholesterol (e.g.,hyperlipidemia and hypercholesterolemia), diarrhea, ovarian diseases(e.g. endometriosis, ovarian cysts, etc.) and as contraceptive agents.Other conditions treatable according to the invention will be apparentto those skilled in the art based upon the disclosure and lists ofcompounds provided.

[0124] The methods and/or products of the invention also are useful intreating conditions specific to central nervous system tissue andnoncentral nervous system tissue. Such conditions can be specific tobreast tissue, gastrointestinal tissue and ovarian tissue. The tissuealso may be other noncentral nervous system tissues. Noncentral nervoussystem tissue includes tissues of the blood and blood forming system:including platelets, blood vessel wall, and bone marrow; cardiovascularsystem: including heart and vascular system; digestive and excretorysystem: including alimentary tract, biliary tract, kidney, liver,pancreas and urinary tract; endocrine system: including adrenal gland,kidney, ovary, pituitary gland, renal gland, salivary gland, sebaceousgland, testis, thymus gland and thyroid gland; muscular system:including muscles that move the body; reproductive system: includingbreast, ovary, penis and uterus; respiratory system: including bronchus,lung and trachea; skeletal system: including bones and joints; tissue,fiber, and integumentary system: including adipose tissue, cartilage,connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hairfollicle, ligament, bone marrow, melanin, melanocyte, mucous membrane,skin, soft tissue, synovial capsule and tendon.

[0125] A pharmaceutical agent, according to this aspect of the inventioncan be any drug that can form a conjugate with a fatty amine or a fattyamine intermediate according to the invention. Preferably, the drug hasfree groups reactive with a free amine of the fatty amine or thereactive group of one of the intermediates of the invention. Morepreferably, the drug has a free —OH (hydroxyl group), —NH₂ (primaryamino group), —NHR′ (secondary amino group wherein R′ is alkyl, aryl,etc.), —SH (thio group) or —CO₂H (carboxylic acid) group.

[0126] A pharmaceutical agent moiety, according to the invention, is apharmaceutical agent that has lost a hydrogen, in the case of, forexample, an —OH, —NH₂, —NHR′, or —CO₂H group.

[0127] As used herein, pharmaceutical agents may be selected from, butare not limited to, the following agents: adrenergic agent;adrenocortical steroid; adrenocortical suppressant; amine deterrent;aldosterone antagonist; amino acid; ammonia detoxicant; anabolic;analeptic; analgesic; androgen; anesthesia; anesthetic; anorectic;antagonist; anterior pituitary suppressant; anthelmintic; anti-acneagent; anti-adrenergic; anti-allergic; anti-amebic; anti-androgen;anti-anemic; anti-anginal; anti-anxiety; anti-arthritic; anti-asthmatic;anti-atherosclerotic; antibacterial; anticholelithic;anticholelithogenic; anticholinergic; anticoagulant; anticoccidal;anticonvulsant; antidepressant; antidiabetic; antidiarrheal;antidiuretic; antidote; anti-emetic; anti-epileptic; anti-estrogen;antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic;antihemorrhagic; antihistamine; antihyperlipidemia;antihyperlipoproteinemic; antihypertensive; antihypotensive;anti-infective; anti-infective, topical; anti-inflammatory;antikeratinizing agent; antimalarial; antimicrobial; antimigraine;antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic,antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic,antipneumocystic; antiproliferative; antiprostatic hypertrophy;antiprotozoal; antipruritic; antipsychotic; antirheumatic;antischistosomal; antiseborrheic; antisecretory; antispasmodic;antithrombotic; antitussive; anti-ulcerative; anti-urolithic; antiviral;appetite suppressant; benign prostatic hyperplasia therapy agent; bloodglucose regulator; bone resorption inhibitor; bronchodilator; carbonicanhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic;cardiovascular agent; choleretic; cholinergic; cholinergic agonist;cholinesterase deactivator; coccidiostat; cognition adjuvant; cognitionenhancer; depressant; diagnostic aid; diuretic; dopaminergic agent;ectoparasiticide; emetic; enzyme inhibitor; estrogen; fibrinolytic;fluorescent agent; free oxygen radical scavenger; gastrointestinalmotility effector; glucocorticoid; gonad-stimulating principle; hairgrowth stimulant; hemostatic; histamine H2 receptor antagonists;hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive;imaging agent; immunizing agent; immunomodulator; immunoregulator;immunostimulant; immunosuppressant; impotence therapy adjunct;inhibitor; keratolytic; LNRH agonist; liver disorder treatment;luteolysin; memory adjuvant; mental performance enhancer; moodregulator; mucolytic; mucosal protective agent; mydriatic; nasaldecongestant; neuromuscular blocking agent; neuroprotective; NMDAantagonist; non-hormonal sterol derivative; oxytocic; plasminogenactivator; platelet activating factor antagonist; platelet aggregationinhibitor; post-stroke and post-head trauma treatment; potentiator;progestin; prostaglandin; prostate growth inhibitor; prothyrotropin;psychotropic; pulnonary surface; radioactive agent; regulator; relaxant;repartitioning agent; scabicide; sclerosing agent; sedative;sedative-hypnotic; selective adenosine A1 antagonist; serotoninantagonist; serotonin inhibitor; serotonin receptor antagonist; steroid;stimulant; suppressant; agent for treatment of symptomatic multiplesclerosis; synergist; thyroid hormone; thyroid inhibitor; thyromimetic;tranquilizer; agent for treatment of amyotrophic lateral sclerosis;agent for treatment of cerebral ischemia; agent for treatment of Paget'sdisease; agent for treatment of unstable angina; uricosuric;vasoconstrictor; vasodilator; vulnerary; wound healing agent; andxanthine oxidase inhibitor.

[0128] Lists of compounds in each of these categories can be found inU.S. Pat. No. 5,795,909, the disclosure of which is incorporated hereinby reference. Among preferred groups of drugs are anticancer agents,antiinfectives including and antibacterials and antivirals, andneurological agents including antipsychotics. Anticancer agents,antivirals, antipsychotics; and preferred anticancer agents, preferredantivirals, and preferred antipsychotics are as described below.

[0129] Antiinfectives include, but are not limited to, DifloxacinHydrochloride; Lauryl Isoquinolinium Bromide; Moxalactam Disodium;Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Proteaseinhibitors of HIV and other retroviruses; Integrase Inhibitors of HIVand other retroviruses; Cefaclor (Ceclor); Acyclovir (Zovirax);Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin);Ciprofloxacin (Cipro); Aminacrine Hydrochloride; Benzethonium Chloride;Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; CetalkoniumChloride; Cetylpyridinium Chloride: Chlorhexidine Hydrochloride;Clioquinol; Domiphen Bromide; Fenticlor; Fludazonium Chloride; Fuchsin,Basic; Furazolidone; Gentian Violet; Halquinols; Hexachlorophene:Hydrogen Peroxide; Ichthammol; Iinidecyl Iodine; Iodine; IsopropylAmine; Mafenide Acetate; Meralein Sodium; Mercufenol Chloride; Mercury,Ammoniated; Methylbenzethonium Chloride; Nitrofurazone; Nitromersol;Octenidine Hydrochloride; Oxychlorosene; Oxychlorosene Sodium;Parachlorophenol, Camphorated; Potassium Permanganate; Povidone-lodine;Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; Symclosene;Thimerfonate Sodium; Thimerosal; Troclosene Potassium.

[0130] Anti-bacterials include, but are not limited to, Acedapsone;Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; AmdinocillinPivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin;Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium;Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; ApalcillinSodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin;Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; BacampicillinHydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; BacitracinZinc; Bambermycins; Benzoylpas Calcium; Berythromycin; BetamicinSulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride; BispyrithioneMagsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox;Carbenicillin Disodium; Carbenicillin Indanyl Sodium; CarbenicillinPhenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor;Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium;Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium;Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol;Cefixime; Cefinenoxime Hydrochloride; Cefmetnetazole; CefinetazoleSodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium;Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; CefotiamHydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpimizole; CefpimizoleSodium; Cefpiramide; Cefpiramide Sodium; Cefpirome Sulfate; CefpodoximeProxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazldime;Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime;Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; CephacetrileSodium; Cephalexin; Cephalexin Hydrochloride; Cephaloglycin;Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine;Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol;Chloramphenicol Pahnitate; Chloramphenicol Pantothenate Complex;Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate;Chloroxylenol; Chlortetracycline Bisulfate; ChlortetracyclineHydrochloride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochloride;Cirolemycin; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin;Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride;Clindamycin Phosphate; Clofazimine; Cloxacillin Benzathine; CloxacillinSodium; Cloxyquin; Colistimethate Sodium; Colistin Sulfate; Coumermycin;Coumermycin Sodium; Cyclacillin; Cycloserine; Dalfopristin; Dapsone;Daptomycin; Demeclocycline; Demeclocycline Hydrochloride; Demecycline;Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin Sodium;Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline;Doxycycline Calcium; Doxycycline Fosfatex; Doxycycline Hyclate; DroxacinSodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride;Erythromycin; Erythromycin Acistrate; Erythromycin Estolate;Erythromycin Ethylsuccinate; Erythromycin Gluceptate; ErythromycinLactobionate; Erythromycin Propionate; Erythromycin Stearate; EthambutolHydrochloride; Ethionamide; Fleroxacin; Floxacillin; Fludalanine;Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin;Furazolium Chloride; Furazolium Tartrate; Fusidate Sodium; Fusidic Acid;Gentamicin Sulfate; Gloximonam; Gramicidin; Haloprogin; Hetacillin;Hetacillin Potassium; Hexedine; Ibafloxacin; Imipenem; Isoconazole;Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin;Levofuraltadone; Levopropylcillin Potassium; Lexithromycin; Lincomycin;Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochloride;Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline; MeclocyclineSulfosalicylate; Megalomicin Potassium Phosphate; Mequidox; Meropenem;Methacycline; Methacycline Hydrochloride; Methenamine; MethenamineHippurate; Methenamine Mandelate; Methicillin Sodium; Metioprim;Metronidazole Hydrochloride; Metronidazole Phosphate; Mezlocillin;Mezlocillin Sodium; Minocycline; Minocycline Hydrochloride; MirincamycinHydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium; NalidixateSodium; Nalidixic Acid; Natamycin; Nebramycin; Neomycin Palmitate;Neomycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate;Neutramycin; Nifuradene; Nifuraldezone; Nifluratel; Nifuratrone;Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole;Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium;Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam Sodium;Oxolinic Acid; Oxytetracycline; Oxytetracycline Calcium; OxytetracyclineHydrochloride; Paldimycin; Parachlorophenol; Paulomycin; Pefloxacin;Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin GPotassium; Penicillin G Procaine; Penicillin G Sodium; Penicillin V;Penicillin V Benzathine; Penicillin V Hydrabamine; Penicillin VPotassium; Pentizidone Sodium; Phenyl Aminosalicylate; PiperacillinSodium; Pirbenicillin Sodium; Piridicillin Sodium; PirlimycinHydrochloride; Pivampicillin Hydrochloride; Pivampicillin Pamoate;Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin;Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin;Racephenicol; Ramoplanin; Ranimycin; Relomycin; Repromicin; Rifabutin;Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine; Rifaxirnin;Rolitetracycline; Rolitetracycline Nitrate; Rosaramicin; RosaramicinButyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate;Rosaramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline;Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafingin; Sisomicin;Sisomicin Sulfate; Sparfloxacin; Spectinomycin Hydrochloride;Spiramycin; Stallimycin Hydrochloride; Steffimycin; StreptomycinSulfate; Streptonicozid; Sulfabenz; Sulfabenzamide; Sulfacetamide;Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium;Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine;Sulfamethizole; Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole;Sulfanilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomizole;Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl;Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; SuncillinSodium; Talampicillin Hydrochloride; Teicoplanin; TemafloxacinHydrochloride; Temocillin; Tetracycline; Tetracycline Hydrochloride;Tetracycline Phosphate Complex; Tetroxoprim; Thiamphenicol;Thiphencillin Potassium; Ticarcillin Cresyl Sodium; TicarcillinDisodium; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride;Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; TrimethoprimSulfate; Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate;Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Virginiamycin; andZorbamycin.

[0131] The invention encompasses the preparation and use of fattyamine-anticancer pharmaceutical agents. The compounds useful in theinvention may be delivered in the form of anticancer cocktails. Ananticancer cocktail is a mixture of any one of the compounds useful withthis invention with another anticancer agent such as an anticancer drug,a cytokine, and/or supplementary potentiating agent(s). The use ofcocktails in the treatment of cancer is routine. In this embodiment, acommon administration vehicle (e.g., pill, tablet, implant, injectablesolution, etc.) would contain both the fatty amine-anticancerpharmaceutical conjugate useful in this invention and/or supplementarypotentiating agent.

[0132] Anticancer agents include, but are not limited to, Antineoplasticagents such as: Acivicin; Aclarubicin; Acodazole Hydrochloride;Acronine; Adozelesin; Adriamycin; Aldesleukin; Alitretinoin; AllopurinolSodium; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide;Amsacrine; Anastrozole; Annonaceous Acetogenins; Anthramycin; Asimicin;Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat;Benzodepa; Bexarotene; Bicalutamide; Bisantrene Hydrochloride; BisnafideDimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine;Bullatacin; Busulfan; Cabergoline; Cactinomycin; Calusterone;Caracemide; Carbetimer; Carboplatin; Carmustine; CarubicinHydrochloride; Carzelesin; Cedefingol; Celecoxib; Chlorambucil;Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate;Cyclophosphamide; Cytarabine; Dacarbazine; DACA(N-[2-(Dimethyl-amino)ethyl]acridine-4-carboxamide); Dactinomycin;Daunorubicin Hydrochloride; Daunomycin; Decitabine; Denileukin Diftitox;Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel;Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; DroloxifeneCitrate; Dromostanolone Propionate; Duazomycin; Edatrexate; EflornithineHydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride;Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized OilI 131; Etoposide; Etoposide Phosphate; Etoprine; FadrozoleHydrochloride; Fazarabine; Fenretinide; Floxuridine; FludarabinePhosphate; Fluorouracil; 5-FdUMP; Flurocitabine; Fosquidone; FostriecinSodium; FK-317; FK-973; FR-66979; FR-900482; Gemcitabine; GemcitabineHydrochloride; Gemtuzumab Ozogamicin; Gold Au 198; Goserelin Acetate;Guanacone; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide;Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-n1;Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-I b;Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole;Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium;Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine;Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate;Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium;Methoxsalen; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;Mitogillin; Mitomalcin; Mitomycin; Mytomycin C; Mitosper; Mitotane;Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;Oprelvekin; Ormaplatin; Oxisuran; Paclitaxel; Pamidronate Disodium;Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate;Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride;Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine;Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride;Pyrazofirin; Riboprine; Rituximab; Rogletimide; Rolliniastatin;Safingol; Safingol Hydrochloride; Samarium/Lexidronam; Semustine;Simtrazene; Sparfosate Sodium; Sparsomycin; SpirogermaniumHydrochloride; Spiromustine; Spiroplatin; Squamocin; Squamotacin;Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; TeloxantroneHydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;Thiamiprine; Thioguanine; Thiotepa; Thymitaq; Tiazofurin; Tirapazamine;Tomudex; TOP-53; Topotecan Hydrochloride; Toremifene Citrate;Trastuzumab; Trestolone Acetate; Triciribine Phosphate; Trimetrexate;Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; UracilMustard; Uredepa; Valrubicin; Vapreotide; Verteporfin; Vinblastine;Vinblastine Sulfate; Vincristine; Vincristine Sulfate; Vindesine;Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate;Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate;Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; ZorubicinHydrochloride; 2-Chlorodeoxyadenosine; 2′-Deoxyformycin;9-aminocamptothecin; raltitrexed; N-propargyl-5,8-dideazafolic acid;2-chloro-2′-arabinofluoro-2′-deoxyadenosine; 2-chloro-2′-deoxyadenosine;anisomycin; trichostatin A; hPRL-G129R; CEP-751; linomide; sulfurmustard; nitrogen mustard (mechlor ethamine); cyclophosphamide;melphalan; chlorambucil; ifosfamide; busulfan; N-methyl-N-nitrosourea(MNU); N,N′-Bis(2-chloroethyl)-N-nitrosourea (BCNU);N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea (CCNU);N-(2-chloroethyl)-N′-(trans-4-methylcyclohexyl-N-nitrosourea (MeCCNU);N-(2-chloroethyl)-N′-(diethyl)ethylphosphonate-N-nitrosourea(fotemustine); streptozotocin; diacarbazine (DTIC); mitozolomide;temozolomide; thiotepa; mitomycin C; AZQ; adozelesin; Cisplatin;Carboplatin; Ormaplatin; Oxaliplatin; C1-973; DWA 2114R; JM216; JM335;Bis(platinum); tomudex; azacitidine; cytarabine; gemcitabine;6-Mercaptopurine; 6-Thioguanine; Hypoxanthine; teniposide; 9-aminocamptothecin; Topotecan; CPT-11; Doxorubicin; Daunomycin; Epirubicin;darubicin; mitoxantrone; losoxantrone; Dactinomycin (Actinomycin D);amsacrine; pyrazoloacridine; all-trans retinol;14-hydroxy-retro-retinol; all-trans retinoic acid; N-(4-Hydroxyphenyl)retinamide; 13-cis retinoic acid; 3-Methyl TTNEB; 9-cis retinoic acid;fludarabine (2-F-ara-AMP); and 2-chlorodeoxyadenosine (2-Cda).

[0133] Other anti-neoplastic compounds include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bleomycin A₂; bleomycin B₂; bropirimine;budotitane; buthionine sulfoximine; calcipotriol; calphostin C;camptothecin derivatives (e.g., 10-hydroxy-camptothecin); canarypoxIL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; caseinkinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;cladribine; clomifene analogues; clotrimazole; collismycin A;collismycin B; combretastatin A4; combretastatin analogue; conagenin;crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives;curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabineocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;dehydrodidemnin B; 2′deoxycoformycin (DCF); deslorelin; dexifosfamide;dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin;diphenyl spiromustine; discodermolide; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epothilones (A, R=H; B, R=Me); epithilones; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide; etoposide 4′-phosphate (etopofos); exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; homoharringtonine (HHT);hypericin; ibandronic acid; idarubicin; idoxifene; idramantone;ilmofosine; ilomastat; imidazoacridones; imiquimod; inununostimulantpeptides; insulin-like growth factor-1 receptor inhibitor; interferonagonists; interferons; interleukins; iobenguane; iododoxorubicin;ipomeanol, 4-; irinotecan; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline;lytic peptides; maitansine; mannostatin A; marimastat; masoprocol;maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;menogaril; merbarone; meterelin; methioninase; metoclopramide; MIFinhibitor; mifepristone; miltefosine; mirimostim; mismatched doublestranded RNA; mithracin; mitoguazone; mitolactol; mitomycin analogues;mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone;mofarotene; molgramostim; monoclonal antibody, human chorionicgonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk;mopidamol; multiple drug resistance gene inhibitor; multiple tumorsuppressor 1-based therapy; mustard anticancer agent; mycaperoxide B;mycobacterial cell wall extract; myriaporone; N-acetyldinaline;N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine;napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronicacid; neutral endopeptidase; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;octreotide; okicenone; oligonucleotides; onapristone; ondansetron;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perfosfamide; perillyl amine;phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetinB; plasminogen activator inhibitor; platinum complex; platinumcompounds; platinum-triamine complex; podophyllotoxin; porfimer sodium;porfiromycin; propyl bis-acridone; prostaglandin J2; proteasomeinhibitors; protein A-based immune modulator; protein kinase Cinhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl proteintransferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptinedemethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RIIretinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; signal transductionmodulators; single chain antigen binding protein; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thalidomide; thiocoraline; thrombopoietin; thrombopoietinmimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;titanocene dichloride; topotecan; topsentin; toremifene; totipotent stemcell factor; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; vector system, erythrocyte genetherapy; velaresol; veramine; verdins; verteporfin; vinorelbine;vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; andzinostatin stimalamer.

[0134] Other anticancer agents include, but are not limited to,antiproliferative agents (e.g., Piritrexim Isothionate), antiprostatichypertrophy agents (e.g., Sitogluside), benign prostatic hyperplasiatherapy agents: (e.g., Tamsulosin Hydrochloride), Prostate growthinhibitors (e.g., Pentomone) and radioactive agents: Fibrinogen 1 125;Fludeoxyglucose F 18; Fluorodopa F 18; Insulin I 125; Insulin I 131;Iobenguane I 123; Iodipamide Sodium I 131; Iodoantipyrine I 131;Iodocholesterol I 131; Iodohippurate Sodium I 123; Iodohippurate SodiumI 125; Iodohippurate Sodium I 131; Iodopyracet I 125; Iodopyracet I 131;Iofetamine Hydrochloride I 123; Iomethin I 125; Iomethin I 131;Iothalamate Sodium I 125; Iothalamate Sodium I 131; Iotyrosine 1 131;Liothyronine I 125; Liothyronine I 131; Merisoprol Acetate Hg 197;Merisoprol Acetate Hg 203; Merisoprol Hg 197; Selenomethionine Se 75;Technetium Tc 99m Antimony Trisulfide Colloid; Technetium Tc 99mBicisate; Technetium Tc 99m Disofenin; Technetium Tc 99m Etidronate;Technetium Tc 99m Exametazime; Technetium Tc 99m Furifosmin; TechnetiumTc 99m Gluceptate; Technetium Tc 99m Lidofenin; Technetium Tc 99mMebrofenin; Technetium Tc 99m Medronate; Technetium Tc 99m MedronateDisodium; Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidronate;Technetium Tc 99m Pentetate; Technetium Tc 99m Pentetate CalciumTrisodium; Technetium Tc 99m Sestamibi; Technetium Tc 99m Siboroxime;Technetium Tc 99m Succimer; Technetium Tc 99m Sulfur Colloid; TechnetiumTc 99m Teboroxime; Technetium Tc 99m Tetrofosmin; Technetium Tc 99mTiatide; Thyroxine 1 125; Thyroxine 1 131; Tolpovidone 1 131; Triolein 1125; and Triolein 1 131.

[0135] Anticancer Supplementary Potentiating Agents also may beconjugated to fatty amine moieties. Such agents include, but are notlimited to, Tricyclic anti-depressant drugs (e.g., imipramine,desipramine, amitryptyline, clomipramine, trimipramine, doxepin,nortriptyline, protriptyline, amoxapine and maprotiline); non-tricyclicanti-depressant drugs (e.g., sertraline, trazodone and citalopram); Ca⁺⁺antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine);Calmodulin inhibitors (e.g., prenylamine, trifluoroperazine andclomipramine); Amphotericin B; Triparanol analogues (e.g., tamoxifen);antiarrhythmic drugs (e.g., quinidine); antihypertensive drugs (e.g.,reserpine); Thiol depleters (e.g., buthionine and sulfoximine) andMultiple Drug Resistance reducing agents such as Cremaphor EL. Thecompounds of the invention also can be administered with cytokines suchas granulocyte colony stimulating factor.

[0136] Preferred anticancer agents (some with their MTDs shown inparentheses) include, but are not limited to, annonaceous acetogenins;asimicin; rolliniastatin; guanacone, squamocin, bullatacin; squamotacin;taxanes; paclitaxel (225 mg/m²); gemcitabine (1000 mg/m²); methotrexate(15 gm/m² i.v.+leuco. <500 mg/m² i.v. w/o leuco); FR-900482; FK-973; 3,FR-66979; FK-317; 5-FU (500 mg/m²/day×5 days); FUDR (100 mg/kg×5 inmice, 0.6 mg/kg/day in human i.a.); FdUMP; Hydroxyurca (35 mg/kg/d inman); Docetaxel (60-100 mg/m²); discodermolide; epothilones; vincristine(1.4 mg/m²); vinblastine (escalating: 3.3-11.1 mg/m², or rarely to 18.5mg/m²); vinorelbine (30 mg/m²/wk); meta-pac; irinotecan (50-150 mg/m²,1×/wk depending on patient response); SN-38 (˜100 times more potent thanIrinotecan); 10-OH campto; topotecan (1.5 mg/m²/day in humans, 1×iv LD10mice=75 mg/m²); etoposide (100 mg/m² in man); adriamycin; flavopiridol;Cis-Pt (100 mg/m² in man); carbo-Pt (360 mg/m² in man); bleomycin (20mg/m²); mitomycin C (20 mg/m²); mithramycin (30 μg/kg); capecitabine(2.5 g/m² orally); cytarabine (100 mg/m²/day); 2-Cl-2′deoxyadenosine;Fludarabine-PO₄ (25 mg/m²/day,×5 days); mitoxantrone (12-14 mg/m²);mitozolomide (>400 mg/m²); Pentostatin; and Tomudex.

[0137] Particularly preferred pharmaceutical agents include taxanes. Asused herein, a taxane is a molecule that possesses the followingtricyclic (A, B, and C) carbon-atom connectivity network:

[0138] shown with optional methyl groups and may incorporatecarbon-carbon multiple bonds, substituents, functional groups, andadditional rings. Taxanes are conventionally numbered as shown above.

[0139] A taxoid is a molecule structurally related to a taxane in whichthe above taxane carbon-atom connectivity network is altered, forexample, by cleavage of one or more of the carbocyclic rings, bydeletion or addition of carbon substituents, by connection of carbonatoms normally not bonded to each other, by disconnection of carbonatoms normally bonded to each other, or by some other reorganization ofor adjustment to the taxane carbon-atom connectivity network, but inwhich one or more structural features characteristic of the taxanecarbon-atom connectivity network are conserved.

[0140] Paclitaxel and docetaxel are both taxanes and are preferredanticancer pharmaceutical agents in the invention. A preferredpharmaceutical agent useful in the present invention is flavopiridol,which is a non-taxane anticancer pharmaceutical agent.

[0141] As used herein, “annonaceous acetogenin” includes inhibitors ofthe enzyme NADH:ubiquinone oxidoreductase, including, but not limitedto: asimicin (CAS Reg. No. 102989-24-2), rolliniastatin asimicin (CASReg. No. 157966-79-5), guanacone (CAS Reg. No. 212616-61-0), squamocinasimicin (CAS Reg. No. 120298-30-8), bullatacin asimicin (CAS Reg. No.123123-32-0), and squamotacin asimicin (CAS Reg. No. 174158-66-8).

[0142] As used herein the mitomycins are a family of compounds that arehighly potent DNA cross-linking agents, and include, but are not limitedto: mytomycin C, FR-66979, FR-900482, FK-973, and FK-317.

[0143] The conjugates of the invention are administered in effectiveamounts to a subject in need of treatment with the pharmaceuticalagents. Such subjects and such amounts can be determined by those ofordinary skill in the art. For example, a subject in need ofantiproliferative treatment includes subjects diagnosed with a mammalianproliferative disorder (e.g. cancer) or being suspected of having,developing or suspected of developing a mammalian proliferativedisorder. Methods for identifying subject suspected of havingproliferative disease may include physical examination, biopsy,subject's family medical history, subject's medical history, or a numberof imaging technologies such as mammography, magnetic resonance imaging,magnetic resonance spectroscopy, or positron emission tomography.Diagnostic methods for proliferative disease and the clinicaldelineation of proliferative diseases are well-known to those of skillin the medical arts.

[0144] An effective amount means that amount necessary to delay theonset of, inhibit the progression of, halt altogether the onset orprogression of or diagnose the particular condition being treated. Forexample, an effective amount for treating cancer will be that amountnecessary to inhibit altogether, delay, or slow mammalian cancer cellproliferation in situ.

[0145] When administered to a subject, effective amounts will depend, ofcourse, on the particular condition being treated; the severity of thecondition; individual patient parameters including age, physicalcondition, size and weight; concurrent treatment; frequency oftreatment; and the mode of administration. These factors are well knownto those of ordinary skill in the art and can be addressed with no morethan routine experimentation. It is preferred generally that a maximumdose be used, that is, the highest safe dose according to sound medicaljudgment.

[0146] The maximum tolerated dose (MTD) for any therapeutic compound isidentified as part of its clinical evaluation. For example, phase Itrials can include a determination of the maximum tolerated dose, doselimiting toxicities (DLT) and pharmacokinetics of a test compound.“Maximum tolerated dose,” as used herein, refers to the largest dose ofa pharmaceutical agent that an adult patient can take with safety totreat a particular disease or condition. Thus, the MTD for any Food andDrug Administration (FDA) approved therapeutic compound is known tothose of ordinary skill in the art as a matter of the public record. TheMTD for any particular therapeutic compound may vary according to itsformulation (e.g., injectable formulation, implantable bioerodiblepolymer formulation, oral formulation), route of delivery (e.g.,intravenous, oral, intratumoral), manner of delivery (e.g., infusion,bolus injection), dosing schedule (e.g., hourly, daily, weekly) and thelike. The MTD frequently is defined as the highest dose level at which50% of subjects administered with the drug develop a dose limitingtoxicity. The doses for anti-neoplastic pharmaceutical agents found inthe Physicians Desk Reference (PDR) are defined as the MTD for thoseagents. The MTD is further defined to include only doses for drugs(including anti-neoplastics) used as single agents and withoutadditional cellular, genetic, pharmaceutical, or other agents added toalter the MTD. Other definitions which are clinically relevant andgenerally accepted will be known to one of ordinary skill in the art.

[0147] Measurement of maximum tolerated dose may be expressed as weightof drug per weight of subject, weight of drug per body surface area,etc. The MTD of anticancer compounds is frequently expressed as weightper square meters (mg/m²) of body surface area. For example, the MTD forpaclitaxel infusion in humans is 225 mg/m². The most often used clinicaltolerated dose is 175 mg/m². MTD also may be expressed as a doserelative to a time component, such as weight of drug per body surfacearea per day.

[0148] For therapeutics which have not yet been subjected to humanclinical trials, or subjected to any determination of the MTD in humans(e.g., experimental or highly toxic compounds), one of skill in the artcan estimate the MTD by using animal models. Calculation of MTD inanimals may be based on a number of physiological parameters, such asdeath, particular toxicities, drug induced weight loss, etc. Using deathas an endpoint, the MTD may be the dose given test animals in which eachmember of the test group survived. Using toxicity as an endpoint, theMTD may be the dose at which moderate but not severe toxicity isobserved. Using weight loss as an endpoint, the MTD may be the doseabove which a certain percent change in body weight is induced. Othermethods for determining MTDs using animal models and various endpointsare known to one of ordinary skill in the art. Correlation of animalMTDs to human MTDs for a therapeutic compound is an accepted practice inthe pharmaceutical arts.

[0149] For example, it has been determined that a conjugate of DHA andpaclitaxel (Taxoprexin™) has a maximum tolerated dose in animals (mice,rats and dogs) which is about 4-5 times greater (by weight) thanpaclitaxel alone or about 3-4 times greater (by molarity) thanpaclitaxel alone.

[0150] In one aspect of the invention the subjects have a need fortreatment with an antiviral agent. One of ordinary skill in the art isfamiliar with a variety of antiviral agents which are used in themedical arts to treat viral infections. Such agents include, but are notlimited to, nucleoside analogs, nonnucleoside reverse transcriptaseinhibitors, protease inhibitors, integrase inhibitors, including, forexample, the following: Acemannan; Acyclovir; Acyclovir Sodium;Adefovir; Alovudine; Alvircept Sudotox; Amantadine Hydrochloride;Aranotin; Arildone; Atevirdine Mesylate; Avridine; Cidofovir;Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate;Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime;Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine;Fosarilate; Foscamet Sodium; Fosfonet Sodium; Ganciclovir; GanciclovirSodium; Idoxuridine; Indinavir; Kethoxal; Lamivudine; Lobucavir;Memotine Hydrochloride; Methisazone; Nelfinavir; Nevirapine;Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Ritonavir;Saquinavir Mesylate; Somantadine Hydrochloride; Sorivudine; Statolon;Stavudine; Tilorone Hydrochloride; Trifluridine; ValacyclovirHydrochloride; Vidarabine; Vidarabine Phosphate; Vidarabine SodiumPhosphate; Viroxime; Zalcitabine; Zidovudine; Zinviroxime and integraseinhibitors.

[0151] The invention thus is used in connection with treating subjectshaving, suspected of having, developing or suspected of developing aviral infection, including, for example, a retroviral infection such asHIV. A preferred antiviral agent useful in the present invention isadefovir. Adefovir, [9-(2-phosphonomethyoxylethyl) adenine (PMEA)] is anucleotide analog that has been shown to be useful for, among otheruses, as a reverse transcriptase inhibitor.

[0152] An effective amount in the case of a virus means that amountnecessary to delay the onset of, inhibit the progression of or haltaltogether the onset or progression of the viral infection. Inparticular embodiments, the infection is a retroviral infection, andmost particularly an HIV infection. In general, an effective amount willbe that amount necessary to inhibit the symptoms or physiological (e.g.,immunological or viral) characteristics of the viral infection, any ofwhich otherwise would have occurred in a subject experiencing a viralinfection absent the treatment of the invention. Several parameters maybe used to assess reduction of viral infection, including inhibitedviral replication, a lessened decrease of CD4+ T cell counts, astabilization of CD4+ T cell count or even an increased CD4+ T cellcount, and/or an inhibited increase of viral load or even a decreasedviral load, for example, as compared to pretreatment patient parameters,untreated patients or, in the case of treatment with cocktails, patientshaving a viral infection treated with antiviral agents alone (i.e.without the conjugate of the invention). These parameters can bemonitored using standard diagnostic procedures including ELISA,polymerase chain reaction (PCR and RT-PCR), and flow cytometry.

[0153] In one aspect of the invention, subjects having a psychosis aretreated. One of ordinary skill in the art is familiar with a variety ofantipsychotic agents which are used in the medical arts to treatpsychoses such as schizophrenia. Antipsychotic agents include, but arenot limited to, Acetophenazine Maleate; Alentemol Hydrobromide;Alpertine; Azaperone; Batelapine Maleate; Benperidol; BenzindopyrineHydrochloride; Brofoxine; Bromperidol; Bromperidol Decanoate; ButaclamolHydrochloride; Butaperazine; Butaperazine Maleate; Carphenazine Maleate;Carvotroline Hydrochloride; Chlorpromazine; ChlorpromazineHydrochloride; Chlorprothixene; Cinperene; Cintriamide; ClomacranPhosphate; Clopenthixol; Clopimozide; Clopipazan Mesylate; CloroperoneHydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride;Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate; FluphenazineEnanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene;Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol;Haloperidol Decanoate; Iloperidone; Iloperidoline Hydrochloride;Lenperone; Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate;Metiapine; Milenperone; Milipertine; Molindone Hydrochloride; NaranolHydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine;Oxiperomide; Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide;Pinoxepin Hydrochloride; Pipamperone; Piperacetazine; PipotiazinePalmitate; Piquindone Hydrochloride; Prochlorperazine Edisylate;Prochlorperazine Maleate; Promazine Hydrochloride; Quetiapine;Remoxipride; Remoxipride Hydrochloride; Risperidone; RimcazoleHydrochloride; Seperidol Hydrochloride; Sertindol; Setoperone;Spiperone; Thioridazine; Thioridazine Hydrochloride; Thiothixene;Thiothixene Hydrochloride; Tioperidone Hydrochloride; TiospironeHydrochloride; Trifluoperazine Hydrochloride; Trifluperidol;Triflupromazine; Triflupromazine Hydrochloride; and ZiprasidoneHydrochloride.

[0154] Preferred antipsychotics include, but are not limited to,Lorazepam; chlordiazepoxide; clorazepate; diazepam; alprazolam;hydroxyzine; buspirone; venlafaxine; mephobarbital; meprobamate;doxepin; perphenazine; hydroxyzine pamoate; venlafaxine; mirtazapine;nefazodone; bupropion; phenelzine; tranylcypromine; citalopram;paraxefine; sertraline; amitrptyline; protriptyline; divalproex;clonazepam; clozapine; haloperidol; loxapine; molindone; thiothixene;pimozide; risperidone; quefiapine; thiothixen; olanzapine; quetiapine;prochlorperazine; mesoridazin; trifluoperazine; chlorpromazine;perphenazine; and fluvoxamine. Most preferred antipsychotics include:clozapine; venlafaxine; risperidone; quefiapine; thiothixen; andolanzapine.

[0155] An effective amount in the case of psychosis means that amountalone or with multiple doses, necessary to delay the onset of, inhibitcompletely or lessen the progression of or halt altogether the onset orprogression of the psychotic condition such as schizophrenia. Ingeneral, an effective amount will be that amount necessary to inhibiteither negative or positive symptoms of the psychotic condition, andpreferably both negative and positive symptoms of the psychoticcondition such as schizophrenia. The inhibition of the negative and/orpositive symptoms of schizophrenia can be monitored by standardpsychiatric evaluation of the subject over time. In addition, otherphysiological methods for monitoring the changes in brain function whichaccompany symptoms of schizophrenia also can be employed to monitor theinhibition of the symptoms. For example, the state of advancement ofschizophrenia can be assessed using magnetic resonance imaging (MRI)(see, e.g., DeLisi et al., (Psychiatry Res. 74(3):129-140, 1997) orpositron emission tomography (PET) (see, e.g., Sabri et al., Lancet349:1735-1739, 1997; Andreasen et al., Lancet 349:1730-1734, 1997). Whenadministered to a subject, effective amounts will depend, of course, onthe particular condition being treated; the severity of the condition;individual patient parameters including age, physical condition, sizeand weight; concurrent treatment; frequency of treatment; and the modeof administration. These factors are well known to those of ordinaryskill in the art and can be addressed with no more than routineexperimentation. It is preferred generally that a maximum dose be used,that is, the highest safe dose according to sound medical judgment.

[0156] In general, dosage may be adjusted appropriately to achievedesired drug levels, locally or systemically. Generally, daily oraldoses of conjugates will be from about 0.001 mg/kg per day to 1000 mg/kgper day, preferably 0.01 mg/kg to 10 mg/kg. It is expected that IV dosesin the same range will be effective. The determination of appropriatedose ranges is routine to those of skill in the art, and can beperformed with no more than routine experimentation. In the event thatthe response in a subject is insufficient at such doses, even higherdoses (or effective higher doses by a different, more localized deliveryroute) may be employed to the extent that patient tolerance permits.Continuous IV dosing over, for example 24 hours or multiple doses perday also are contemplated to achieve appropriate systemic levels ofcompounds.

[0157] Pharmaceutical preparations and compositions herein which containanticancer, antiviral or antipsychotic compounds optionally can containadditional anticancer, antiviral or antipsychotic compounds respectively(i.e. cocktails). The foregoing preparations, formulations andcompositions may be encapsulated by liposomes, according to standardprocedures for preparation of liposomes, but preferably are not.

[0158] The compositions also can contain other components useful informulating pharmaceutical preparations for administration to humans,including surfactants, solvents, preservatives, diluents, and the like,all of which are standard in the pharmaceutical arts.

[0159] Suitable surfactants for use with the present invention includenonionic agents, such as long-chain fatty acids and theirwater-insoluble derivatives. These include fatty amines such as laurylcetyl and stearyl amine, glyceryl esters such as the naturally occurringmono-, di- and triglycerides, and fatty acid esters of fatty amines,such as propylene glycol, polyethylene glycol, sorbitan, sucrose andcholesterol. Also useful are compounds that are those that havepolyoxyethylene groups added through an ether linkage with an aminegroup. Compounds that are particularly useful in the present inventioninclude the polyoxyethylene sorbitan fatty acid esters andpolyoxyethylene glycerol and steroidal esters. Particularly preferredsurfactants are Cremophor® EL and Cremophor® EL-P, which arepolyoxyethylated castor oil surfactants.

[0160] It is contemplated that other surfactants may be used tosolubilize the compositions described herein. For example, it iscontemplated that polysorbate 80, polysorbate 20, sodium laurate, sodiumoleate, and sorbitan monooleate may be useful in certain embodiments ofthe present invention. Anionic surfactants may also be useful in thepractice of the present invention. Examples of these include, but arenot limited to, sodium cholate, sodium lauryl sulfate, sodiumdeoxycholate, sodium laurate, sodium oleate, and potassium laurate.

[0161] In certain embodiments, dehydrated ethanol is used as a solventfor the compositions described herein. In other embodiments, glycolssuch as propylene glycol or polyethylene glycol are within the scope ofthe invention. Simple complex polyols may also be suitable solvents.Moreover, the use of non-dehydrated amines may also be suitable withinthe scope of the present invention. It is recognized that thedetermination of a solvent and its proper concentration to fullysolubilize the conjugate, such as the fatty amine-anticancer, fattyamine-antiviral, and fatty amine-antipsychotic compositions is withinthe scope of a skilled artisan, and would not require undueexperimentation.

[0162] When administered, the formulations of the invention are appliedin pharmaceutically acceptable compositions. Such preparations mayroutinely contain salts, buffering agents, preservatives, compatiblecarriers, and optionally other therapeutic ingredients. When used inmedicine the salts should be pharmaceutically acceptable, butnon-pharmaceutically acceptable salts may conveniently be used toprepare pharmaceutically acceptable salts thereof and are not excludedfrom the scope of the invention. Such pharmacologically andpharmaceutically acceptable salts include, but are not limited to, thoseprepared from the following acids: hydrochloric, hydrobromic, sulphuric,nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic,tartaric, citric, methane sulfonic, formic, malonic, succinic,naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceuticallyacceptable salts can be prepared as alkaline metal or alkaline earthsalts, such as sodium, potassium or calcium salts.

[0163] Suitable buffering agents include: acetic acid and a salt (1-2%W/V); citric acid and a salt (1-3% W/V); and phosphoric acid and a salt(0.8-2% W/V).

[0164] Suitable preservatives include benzalkonium chloride (0.003-0.03%W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) andthimerosal (0.004-0.02% W/V).

[0165] The active compounds of the present invention may be apharmaceutical composition having a therapeutically effective amount ofa conjugate of the invention optionally included in apharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier” as used herein means one or morecompatible solid or liquid filler, dilutants or encapsulating substanceswhich are suitable for administration to a human or other animal. Theterm “carrier” denotes an organic or inorganic ingredient, natural orsynthetic, with which the active ingredient is combined to facilitatethe application. The components of the pharmaceutical compositions arecapable of being commingled with the molecules of the present invention,and with each other, in a manner such that there is no interaction whichwould substantially impair the desired pharmaceutical efficacy.

[0166] Compositions suitable for parenteral administration convenientlycomprise a sterile preparation of the conjugates of the invention. Thispreparation may be formulated according to known methods. Formulationsfor taxanes can be found in Chapter 9 of Tall: Science and Applications,CRC Press, Inc., 2000 Corporate Boulevard, N.W., Boca Raton, Fla. 33431.In general, Tall has been formulated as a 6 mg/ml Cremophor EL(polyoxyethylated castor oil)/ethanol mixture, which is diluted to finalvolume with normal saline or 5% dextrose. A 15 mg/ml solution oftaxotere has been formulated in polysorbate 80 (polyoxyethylenesorbitanmonooleate)/ethanol mixture, diluted with 5% dextrose.

[0167] The sterile preparation thus may be a sterile solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono or di-glycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.Carrier formulations suitable for oral, subcutaneous, intravenous,intramuscular, etc. can be found in Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa.

[0168] A subject, as used herein, means humans, primates, horses, cows,pigs, sheep, goats, dogs, cats, and rodents.

[0169] A variety of administration routes are available. The particularmode selected will depend of course, upon the particular drug selected,the severity of the disease state being treated and the dosage requiredfor therapeutic efficacy. The methods of this invention, generallyspeaking, may be practiced using any mode of administration that ismedically acceptable, meaning any mode that produces effective levels ofthe active compounds without causing clinically unacceptable adverseeffects. Such modes of administration include oral, rectal, sublingual,topical, nasal, transdermal or parenteral routes. The term “parenteral”includes subcutaneous, intravenous, intramuscular, or infusion.Intravenous and oral routes are preferred.

[0170] The compositions may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. All methods include the step of bringing the conjugates of theinvention into association with a carrier which constitutes one or moreaccessory ingredients. In general, the compositions are prepared byuniformly and intimately bringing the compounds into association with aliquid carrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product.

[0171] Compositions suitable for oral administration may be presented asdiscrete units such as capsules, cachets, tablets, or lozenges, eachcontaining a predetermined amount of the active compound. Othercompositions include suspensions in aqueous liquors or non-aqueousliquids such as a syrup, an elixir, or an emulsion.

[0172] Other delivery systems can include time-release, delayed releaseor sustained release delivery systems. Such systems can avoid repeatedadministrations of the active compounds of the invention, increasingconvenience to the subject and the physician. Many types of releasedelivery systems are available and known to those of ordinary skill inthe art. They include polymer based systems such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; nonpolymersystems that are lipids including sterols such as cholesterol,cholesterol esters and fatty acids or neutral fats such as mono-, di-and triglycerides; hydrogel release systems; silastic systems; peptidebased systems; wax coatings, compressed tablets using conventionalbinders and excipients, partially fused implants and the like. Inaddition, a pump-based hardware delivery system can be used, some ofwhich are adapted for implantation.

[0173] A long-term sustained release implant also may be used.“Long-term” release, as used herein, means that the implant isconstructed and arranged to deliver therapeutic levels of the activeingredient for at least 30 days, and preferably 60 days. Long-termsustained release implants are well known to those of ordinary skill inthe art and include some of the release systems described above.

[0174] Those skilled in the art will be able to recognize with no morethan routine experimentation numerous equivalents to the specificproducts and processes described above. Such equivalents are intended tobe included within the scope of the appended claims.

[0175] The following examples are provided to guide those skilled in theart. Various changes and modifications may be made, as will be evidentto those skilled in the art, and are within the scope of the invention.Fatty acids and alcohols were obtained from Nu-Chek Prep, Inc. (Elysian,Minn.). The reagents and solvents used are readily available, forexample, from Aldrich Chemical Co., Inc. (Milwaukee, Wis.), EM Sciences(Cincinnati, Ohio), and VWR Scientific (Bridgeport, N.J.).

EXAMPLES Example 1 Examples of Paclitaxel Conjugates

[0176] The length of the fatty moiety chain is governed by the syntheticprocedure. For example, preparation of the fatty amine from thecorresponding fatty acid (with an even number of carbons) generallyresults in a carbon chain with an odd number of carbons. Alternatively,preparation of the fatty amine from the corresponding fatty alcohol(with an even number of carbons) generally results in a carbon chainwith an even number of carbons. The following paclitaxel-fatty amineconjugates with an even number and odd number of carbons in the fattymoiety, respectively, are prepared in accordance with the methods of theinvention:

Example 2 Preparation of N-methyl Fatty Amine Conjugates

[0177] The conjugates may be prepared with N-methyl group at the aminomoiety of the fatty amine as shown below:

[0178] to prevent internal self-immolative destruction. N-methylatedfatty amines may be prepared from fatty acids using the proceduresdescribed in the Examples and described generally (in Yamada, F., et al.Heterocycles 1986, 24, 1223 and Somei, M., et al. Heterocycles 1987, 26,895., both hereby incorporated by reference).

Example 3 Synthesis of a Fatty Amine-adefovir Conjugate Via a UreaLinkage

[0179] Adefovir (PMEA) was conjugated to a fatty amine using thefollowing procedures:

[0180] wherein Y is methyl or ethyl, (PhO)₂P(O)N₃ is diphenylphosphorylazide, and TMSBr is bromotrimethylsilane. One skilled in the art willappreciate that the number of carbons in the fatty amine moiety of theconjugate is governed by both the starting material and synthetic methodchosen.

Example 4 Synthesis of a Fatty Amine-vincristine Conjugate Via an AmideLinkage

[0181] Vincristine is conjugated to a fatty amine at position 23 at themethyl ester using the following procedure:

[0182] One skilled in the art will appreciate that vinblastine isconjugated to a fatty amine using the same procedure.

Example 5 Synthesis of a Fatty Amine-vincristine Conjugate Via aCarbamate Linkage

[0183] Vincristine is conjugated to a fatty amine at position 4 usingthe following procedure:

[0184] wherein RNHC(O)T is a fatty amine activated with a leaving group.The following fatty amine-vincristine conjugate with a thionocarbamatelinker is prepared following an analogous procedure:

[0185] One skilled in the art will appreciate that vinblastine isconjugated to fatty amines using the same procedures.

Example 6 Synthesis of a Fatty Amine Pharmaceutical Agent Conjugate Viaa Urea Linkage

[0186] An isocyanate was prepared from a fatty acid (equivalent to anactivated fatty amine) and then conjugated to a pharmaceutical agent(XNH₂) using the following procedure:

[0187] wherein (PhO)₂P(O)N₃ is diphenylphosphoryl azide. This processwas generally used to produce conjugates with an odd number of carbonatoms in the fatty amine moiety.

Example 7 Synthesis of Fatty Amine Pharmaceutical Agent Conjugate Via aUrea Linkage

[0188] The fatty amine was conjugated to a pharmaceutical agent (XNH₂)using the following procedure:

[0189] This process was generally used to produce conjugates with aneven number of carbon atoms in the fatty amine moiety.

Example 8 Synthesis of a Fatty Amine Pharmaceutical Agent Conjugate Viaa Guanidine Linkage

[0190] Fatty amines are conjugated to doxorubicin using the followingprocedure:

Example 9 Examples of Etoposide Conjugates

[0191] The following etoposide-fatty amine conjugates are prepared usinganalogous methods to those described above and in the specification:

Example 10 Examples of Clozapine Conjugates

[0192] The following clozapine-fatty amine conjugates are prepared usinganalogous methods to those described above and in the specification:

Example 11 Examples of Gemcitabine Conjugates

[0193] The following gemcitabine-fatty amine conjugates are preparedusing analogous methods to those described above and in thespecification:

Example 12 Examples of Flavopiridol Conjugates

[0194] The following flavopiridol-fatty amine conjugates are preparedusing analogous methods to those described above and in thespecification:

[0195] Similarly, conjugates are prepared with fatty amines conjugatedat the 5 position and at the 3 position of flavopiridol.

Example 13 Examples of Purvalanol Conjugates

[0196] The following purvalanol B-fatty amine conjugates were preparedusing analogous methods to those described above and in thespecification:

[0197] Conjugation at the carboxylic acid moiety of Purvalanol Arequires protection of the free hydroxyl group, which may be routinelyaccomplished by those skilled in the art. One skilled in the art willalso appreciate that fatty amines may also be conjugated to an aminogroup of purvalanol A as well as that the analogous types of fatty amineconjugates may be formed with purvalanol B.

Example 14 Examples of Roscovitine Conjugates

[0198] The following roscovitine-fatty amine conjugates are preparedusing analogous methods to those described above and in thespecification:

[0199] Similarly, conjugates are prepared with fatty amines eitherconjugated to the 1′ guanidinium amine nitrogen or the C6 benzyl aminenitrogen in after protecting the primary hydroxyl group of roscovitine.

Example 15 Synthesis of Fatty Amines with Even-numbered Carbon Chains

[0200] Fatty alcohols having even-numbered carbon chains are typicallyobtained from naturally occurring fatty acids via reduction, and serveas a good source of fatty amines having even-numbered carbon chains.Thus, treatment of an even-numbered carbon chain fatty alcohol withphthalimide under Mitsonubu conditions (PPh3, DEAD, THF) provides thecorresponding N-fatty alkyl phthalimide. Hydrazinolysis of the N-fattyalkyl phthalimide intermediate with hydrazine or methylhydrazineprovides the desired fatty amine having an even-numbered carbon chain asshown:

Example 16 Synthesis of Fatty Amines with Odd-numbered Carbon Chains

[0201] Fatty acids having even-numbered carbon chains, when treated withdiphenyl phosphoryl azide in THF at room temperature, are converted intothe corresponding fatty acyl azide. Curtius rearrangement of the fattyacyl azide intermediate to the corresponding fatty isocyanate isaccomplished by careful heating. The fatty isocyanate intermediate(equivalent to an activated odd-numbered carbon chain fatty amine) iscoupled directly to a pharmaceutical agent possessing either a hydroxylor amino group, without isolation and purification, as shown:

Example 17 N-Methylation of Even-numbered Carbon Chain Fatty Amines

[0202] The even-numbered carbon chain fatty amine (synthesized asdescribed above) are treated with methyl chloroformate, thus providingthe corresponding methyl carbamate. Reduction of the methyl carbamateusing lithium aluminum hydride provides the desired N-methylated fattyamine having an even-numbered carbon chain, as shown:

Example 18 N-Methylation of Odd-numbered Carbon Chain Fatty Amines

[0203] The fatty isocyanate (synthesized as described above) is treatedwith methanol, thus providing the corresponding methyl carbamate.Reduction of the methyl carbamate using lithium aluminum hydrideprovides the desired N-methylated fatty amine having an odd-numberedcarbon chain, as shown:

Example 19 Examples of Adefovir Conjugates

[0204] The following adefovir-fatty amine conjugates were prepared usinganalogous methods to those described above and in the specification:

Example 20 Synthesis of a Fatty Amine-SN-38 Conjugate Via a CarbamateLinkage

[0205] SN-38 is conjugated to a fatty amine at position 20 using thefollowing procedure:

[0206] wherein Et₃SiCl is chlorotriethylsilane, DMF isdimethylformamide, the base is N,N-diisopropylethylamine or4-dimethylaminopyridine, and TBAF is tetra-n-butylammonium fluoride.

Example 21 Example of SN-38 Conjugates

[0207] The following SN-38-fatty amine conjugates are prepared usinganalogous methods to those described above and in the specification:

Example 22 Synthesis of a Fatty Amine-adefovir Conjugate Via aPhosphonamide Linkage

[0208] Adefovir is conjugated to a fatty amine at using the followingprocedure:

[0209] As one skilled in the art will recognize, one equivalent oflinoleyl amine will generally form a conjugate with one fatty aminemoiety and two equivalents of linoleyl amine will generally form aconjugate with two fatty amine moieties.

What is claimed is:
 1. A compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XOH.
 2. Thecompound of claim 1, wherein the fatty amine RNH₂ has a carbon structurethat is the same as a carbon structure of a fatty acid occurringnaturally in humans.
 3. The compound of claim 1, wherein the fatty amineRNH₂ has a carbon structure that is the same as a carbon structure of aC₁₂-C₂₆ fatty acid occurring naturally in humans.
 4. The compound ofclaim 1, wherein the fatty amine RNH₂ has a carbon structure that is thesame as a carbon structure of a C₁₄-C₂₄ fatty acid occurring naturallyin humans.
 5. The compound of claim 1, wherein the fatty amine RNH₂ hasa carbon structure that is the same as a carbon structure of a fattyacid selected from myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 6. The compound of claim 5 wherein the pharmaceuticalagent is an anticancer drug.
 7. The compound of claim 5 wherein thepharmaceutical agent is an antiviral drug.
 8. The compound of claim 5wherein the pharmaceutical agent is an antipsychotic drug.
 9. Thecompound of claim 5 wherein the pharmaceutical agent is paclitaxel. 9.The compound of claim 5 wherein the pharmaceutical agent is paclitaxel.10. The compound of claim 5 wherein the pharmaceutical agent isflavopiridol.
 11. A compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Z isO, a primary amino group, or a secondary amino group, and R′ is H, anion, or a protecting group.
 12. The compound of claim 11, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a fatty acid occurring naturally in humans.
 13. Thecompound of claim 11, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a C₁₂-C₂₆ fatty acidoccurring naturally in humans.
 14. The compound of claim 11, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a C₁₄-C₂₄ fatty acid occurring naturally in humans.
 15. Thecompound of claim 11, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 16. The compound of claim 11, wherein R′ is selected fromH, Na⁺, K⁺, Li⁺, and NH₄ ⁺.
 17. The compound of claim 15 wherein thepharmaceutical agent is an anticancer drug.
 18. The compound of claim 15wherein the pharmaceutical agent is an antiviral drug.
 19. The compoundof claim 15 wherein the pharmaceutical agent is an antipsychotic drug.20. The compound of claim 15 wherein the pharmaceutical agent ispaclitaxel.
 21. The compound of claim 15 wherein the pharmaceuticalagent is flavopiridol.
 22. The compound of claim 15 wherein thepharmaceutical agent is adefovir.
 23. A compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein R isa C₈-C₂₆ fatty group of a fatty amine RNH₂, X is a pharmaceutical agentmoiety of a pharmaceutical agent XZH, wherein Z is O, a primary aminogroup, or a secondary amino group.
 24. The compound of claim 23, whereinthe fatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a C₁₂-C₂₆ fatty acid occurring naturally in humans.
 25. Thecompound of claim 23, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a C₁₄-C₂₄ fatty acidoccurring naturally in humans.
 26. The compound of claim 23, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a fatty acid selected from myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, linolenic acid, arachidonic acid, eicosapentaenoic acid,docosenoic acid, docosatetraenoic acid, docosapenataenoic acid,docosahexaenoic acid, and nervonic acid.
 27. The compound of claim 26wherein the pharmaceutical agent is an anticancer drug.
 28. The compoundof claim 26 wherein the pharmaceutical agent is an antiviral drug. 29.The compound of claim 26 wherein the pharmaceutical agent is anantipsychotic drug.
 30. The compound of claim 26 wherein thepharmaceutical agent is adefovir.
 31. A compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XC(O)OH.
 32. Thecompound of claim 31, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidoccurring naturally in humans.
 33. The compound of claim 31, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a C₁₂-C₂₆ fatty acid occurring naturally in humans.
 34. Thecompound of claim 31, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a C₁₄-C₂₄ fatty acidoccurring naturally in humans.
 35. The compound of claim 31, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a fatty acid selected from myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, linolenic acid, arachidonic acid, eicosapentaenoic acid,docosenoic acid, docosatetraenoic acid, docosapentaenoic acid,docosahexaenoic acid, and nervonic acid.
 36. The compound of claim 35wherein the pharmaceutical agent is an anticancer drug.
 37. The compoundof claim 35 wherein the pharmaceutical agent is an antiviral drug. 38.The compound of claim 35 wherein the pharmaceutical agent is anantipsychotic drug.
 39. A compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XOH.
 40. Thecompound of claim 39, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidoccurring naturally in humans.
 41. The compound of claim 39, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a C₁₂-C₂₆ fatty acid occurring naturally in humans.
 42. Thecompound of claim 39, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a C₁₄-C₂₄ fatty acidoccurring naturally in humans.
 43. The compound of claim 39, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a fatty acid selected from myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, linolenic acid, arachidonic acid, eicosapentaenoic acid,docosenoic acid, docosatetraenoic acid, docosapentaenoic acid,docosahexaenoic acid, and nervonic acid.
 44. The compound of claim 43wherein the pharmaceutical agent is an anticancer drug.
 45. The compoundof claim 43 wherein the pharmaceutical agent is an antiviral drug. 46.The compound of claim 43 wherein the pharmaceutical agent is anantipsychotic drug.
 47. The compound of claim 43 wherein thepharmaceutical agent is paclitaxel.
 48. The compound of claim 43 whereinthe pharmaceutical agent is flavopiridol.
 49. A compound of the formula:R—N═C═O wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂.
 50. Thecompound of claim 49, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 51. A compound of the formula:

wherein R is a C₈-C₂₆ group of a fatty amine RNH₂, R′ is H, an ion, aprotecting group, or a pharmaceutical agent, and T is a leaving group.52. The compound of claim 51, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 53. The compound of claim 51 wherein T is —SCH₃ orpyrazole.
 54. A pharmaceutical preparation comprising a compound of theformula

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, and X is apharmaceutical agent moiety of the pharmaceutical agent XOH, and apharmaceutically acceptable carrier.
 55. The pharmaceutical preparationof claim 54, wherein the fatty amine RNH₂ has a carbon structure that isthe same as a carbon structure of a fatty acid from myristic acid,palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenicacid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoicacid, docosenoic acid, docosatetraenoic acid, docosapentaenoic acid,docosahexaenoic acid, and nervonic acid.
 56. The pharmaceuticalpreparation of claim 55 wherein the pharmaceutical agent is ananticancer drug, an antiviral drug, or an antipsychotic drug.
 57. Thepharmaceutical preparation of claim 55 wherein the pharmaceutical agentis paclitaxel, flavopiridol, or adefovir.
 58. A pharmaceuticalpreparation comprising a compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Z isO, a primary amino group, or a secondary amino group, and R′ is H, anion, or a protecting group, and a pharmaceutically acceptable carrier.59. The pharmaceutical preparation of claim 58, wherein the fatty amineRNH₂ has a carbon structure that is the same as a carbon structure of afatty acid selected from myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 60. The pharmaceutical preparation of claim 58, whereinR′ is H or Na⁺.
 61. The pharmaceutical preparation of claim 59 whereinthe pharmaceutical agent is an anticancer drug, an antiviral drug, or anantipsychotic drug.
 62. The pharmaceutical preparation of claim 59wherein the pharmaceutical agent is paclitaxel, flavopiridol, oradefovir.
 63. A pharmaceutical preparation comprising a compound of theformula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XZH, wherein Z isO, a primary amino group, or a secondary amino group.
 64. Thepharmaceutical preparation of claim 63, wherein the fatty amine RNH₂ hasa carbon structure that is the same as a carbon structure of a fattyacid selected from myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 65. The pharmaceutical preparation of claim 64 whereinthe pharmaceutical agent is an anticancer drug, an antiviral drug, or anantipsychotic drug.
 66. The pharmaceutical preparation of claim 64wherein the pharmaceutical agent is paclitaxel, flavopiridol, oradefovir.
 67. A pharmaceutical preparation comprising a compound of theformula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XC(O)OH and apharmaceutically acceptable carrier.
 68. The pharmaceutical preparationof claim 67, wherein the fatty amine RNH₂ has a carbon structure that isthe same as a carbon structure of a fatty acid selected from myristicacid, palmitic acid, palmitoleic acid, stearic acid, oleic acid,vaccenic acid, linoleic acid, linolenic acid, arachidonic acid,eicosapentaenoic acid, docosenoic acid, docosatetraenoic acid,docosapentaenoic acid, docosahexaenoic acid, and nervonic acid.
 69. Thepharmaceutical preparation of claim 68 wherein the pharmaceutical agentis an anticancer drug, an antiviral drug, or an antipsychotic drug. 70.A pharmaceutical preparation comprising a compound of the formula:

wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂ and X is apharmaceutical agent moiety of a pharmaceutical agent XOH and apharmaceutically acceptable carrier.
 71. The pharmaceutical preparationof claim 70, wherein the fatty amine RNH₂ has a carbon structure that isthe same as a carbon structure of a fatty acid selected from myristicacid, palmitic acid, palmitoleic acid, stearic acid, oleic acid,vaccenic acid, linoleic acid, linolenic acid, arachidonic acid,eicosapentaenoic acid, docosenoic acid, docosatetraenoic acid,docosapentaenoic acid, docosahexaenoic acid, and nervonic acid.
 72. Thepharmaceutical preparation of claim 71 wherein the pharmaceutical agentis an anticancer drug, an antiviral drug, or an antipsychotic drug. 73.The pharmaceutical preparation of claim 71 wherein the pharmaceuticalagent is paclitaxel or flavopiridol.
 74. A method of making a compoundof the formula:

comprising reacting an intermediate of the formula R—N═C═O with apharmaceutical agent of the formula XOH for a time sufficient to formthe compound wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂,and X is a pharmaceutical agent moiety of the pharmaceutical agent ofthe formula XOH.
 75. The method of claim 74, wherein the fatty amineRNH₂ has a carbon structure that is the same as a carbon structure of afatty acid selected from myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 76. The method of claim 75 wherein the pharmaceuticalagent is an anticancer drug, an antiviral drug, or an antipsychoticdrug.
 77. The method of claim 75 wherein the pharmaceutical agent ispaclitaxel, flavopiridol, or adefovir.
 78. A method of making a compoundof the formula:

comprising reacting an intermediate of the formula:

with a the pharmaceutical agent XZH for a time sufficient to form thecompound wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, X is apharmaceutical agent moiety of the pharmaceutical agent XZH, wherein Zis O, a primary amino group, or a secondary amino group, R′ is H, anion, a protecting group or a second pharmaceutical agent, and T is aleaving group.
 79. The method of claim 78, wherein the fatty amine RNH₂has a carbon structure that is the same as a carbon structure of a fattyacid selected from myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 80. The method of claim 79 wherein the pharmaceuticalagent is an anticancer drug, an antiviral drug, or an antipsychoticdrug.
 81. The method of claim 79 wherein the pharmaceutical agent ispaclitaxel, flavopiridol, or adefovir.
 82. A method of making a compoundof the formula:

comprising reacting an intermediate of the formula R—N═C═O with apharmaceutical agent of the formula XZH for a time sufficient to formthe compound wherein R is a C₈-C₂₆ fatty group of a fatty amine RNH₂, Xis a pharmaceutical agent moiety of the pharmaceutical agent of theformula XZH, and Z is O, a primary amino group, or a secondary aminogroup.
 83. The method of claim 82, wherein the fatty amine RNH₂ has acarbon structure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 84. The method of claim 83 wherein the pharmaceuticalagent is an anticancer drug, an antiviral drug, or an antipsychoticdrug.
 85. The method of claim 83 wherein the pharmaceutical agent isadefovir.
 86. A method of making a compound of the formula:

comprising: derivatizing a pharmaceutical agent of the formula XC(O)OHwith a leaving group to form an intermediate; and reacting theintermediate with a fatty amine of the formula RNH₂ for a timesufficient to form the compound wherein R is a C₈-C₂₆ fatty group of thefatty amine, and X is a pharmaceutical agent moiety of thepharmaceutical agent of the formula XC(O)OH.
 87. The method of claim 86,wherein the fatty amine RNH₂ has a carbon structure that is the same asa carbon structure of a fatty acid selected from myristic acid, palmiticacid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid,linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid,docosenoic acid, docosatetraenoic acid, docosapentaenoic acid,docosahexaenoic acid, and nervonic acid.
 88. The method of claim 87wherein the pharmaceutical agent is an anticancer drug, an antiviraldrug, or an antipsychotic drug.
 89. A method of treating a disordercomprising administering to a subject in need of such treatment apharmaceutical preparation comprising a compound of the formula:

and a pharmaceutically acceptable carrier wherein R is a C₈-C₂₆ fattygroup of a fatty amine RNH₂, and X is a pharmaceutical agent moiety ofthe pharmaceutical agent XOH.
 90. The method of claim 89, wherein thefatty amine RNH₂ has a carbon structure that is the same as a carbonstructure of a fatty acid selected from myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, linolenic acid, arachidonic acid, eicosapentaenoic acid,docosenoic acid, docosatetraenoic acid, docosapentaenoic acid,docosahexaenoic acid, and nervonic acid.
 91. The method of claim 90wherein the pharmaceutical agent is an anticancer drug, an antiviraldrug, or an antipsychotic drug.
 92. The method of claim 90 wherein thepharmaceutical agent is paclitaxel, flavopiridol, or adefovir.
 93. Themethod of claim 90 wherein the disorder is a mammalian cellproliferation disorder.
 94. The method of claim 93 wherein thepharmaceutical agent is paclitaxel.
 95. The method of claim 93 whereinthe pharmaceutical agent is flavopiridol.
 96. The method of claim 90wherein the disorder is a mammalian viral disorder.
 97. The method ofclaim 90 wherein the disorder is a mammalian psychiatric disorder.
 98. Amethod of treating a disorder comprising administering to a subject inneed of such treatment a pharmaceutical preparation comprising acompound of the formula:

and a pharmaceutically acceptable carrier wherein R is a C₈-C₂₆ fattygroup of a fatty amine RNH₂, X is a pharmaceutical agent moiety of apharmaceutical agent XZH, wherein Z is O, a primary amino group, or asecondary amino group, and R′ is H, an ion, or a protecting group. 99.The method of claim 98, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 100. The method of claim 99 wherein the pharmaceuticalagent is an anticancer drug, an antiviral drug, or an antipsychoticdrug.
 101. The method of claim 99 wherein the pharmaceutical agent ispaclitaxel, flavopiridol, or adefovir.
 102. The method of claim 99wherein the disorder is a mammalian cell proliferation disorder. 103.The method of claim 102 wherein the pharmaceutical agent is paclitaxel.104. The method of claim 102 wherein the pharmaceutical agent isflavopiridol.
 105. The method of claim 99 wherein the disorder is amammalian viral disorder.
 106. The method of claim 105 wherein thepharmaceutical agent is adefovir.
 107. The method of claim 99 whereinthe disorder is a mammalian psychiatric disorder.
 108. A method oftreating a disorder comprising administering to a subject in need ofsuch treatment a pharmaceutical composition comprising a compound of theformula:

and a pharmaceutically acceptable carrier wherein R is a C₈-C₂₆ fattygroup of a fatty amine RNH₂ and X is a pharmaceutical agent moiety of apharmaceutical agent XZH, Z is a primary amino group or a secondaryamino group.
 109. The method of claim 108, wherein the fatty amine RNH₂has a carbon structure that is the same as a carbon structure of a fattyacid selected from myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 110. The method of claim 109 wherein the pharmaceuticalagent is ananticancer drug, an antiviral drug, or an antipsychotic drug.111. The method of claim 109 wherein the pharmaceutical agent ispaclitaxel, flavopiridol, or adefovir.
 112. The method of claim 109wherein the disorder is a mammalian cell proliferation disorder. 113.The method of claim 109 wherein the disorder is a mammalian viraldisorder.
 114. The method of claim 109 wherein the disorder is amammalian psychiatric disorder.
 115. A method of treating a disordercomprising administering to a subject in need of such treatment apharmaceutical composition comprising a compound of the formula:

and a pharmaceutically acceptable carrier wherein R is a C₈-C₂₆ fattygroup of a fatty amine RNH₂ and X is a pharmaceutical agent moiety of apharmaceutical agent XC(O)OH and a pharmaceutically acceptable carrier.116. The method of claim 115, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 117. The method of claim 116 wherein the pharmaceuticalagent is an anticancer drug, an antiviral drug, or an antipsychoticdrug.
 118. The method of claim 116 wherein the disorder is a mammaliancell proliferation disorder.
 119. The method of claim 115 wherein thedisorder is a mammalian viral disorder.
 120. The method of claim 115wherein the disorder is a mammalian psychiatric disorder.
 121. A methodof treating a disorder comprising administering to a subject in need ofsuch treatment a pharmaceutical composition comprising a compound of theformula:

and a pharmaceutically acceptable carrier wherein R is a C₈-C₂₆ fattygroup of a fatty amine RNH₂ and X is a pharmaceutical agent moiety of apharmaceutical agent XOH and a pharmaceutically acceptable carrier. 122.The method of claim 121, wherein the fatty amine RNH₂ has a carbonstructure that is the same as a carbon structure of a fatty acidselected from myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, linolenic acid,arachidonic acid, eicosapentaenoic acid, docosenoic acid,docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, andnervonic acid.
 123. The method of claim 122 wherein the pharmaceuticalagent is an anticancer drug, an antiviral drug, or an antipsychoticdrug.
 124. The method of claim 122 wherein the pharmaceutical agent ispaclitaxel, flavopiridol, or adefovir.
 125. The method of claim 122wherein the disorder is a mammalian cell proliferation disorder. 126.The method of claim 125 wherein the pharmaceutical agent is paclitaxel.127. The method of claim 125 wherein the pharmaceutical agent isflavopiridol.
 128. The method of claim 125 wherein the disorder is amammalian viral disorder.
 129. The method of claim 125 wherein thedisorder is a mammalian psychiatric disorder.